RNA-Seq analysis reveals new evidence for inflammation-related changes in aged kidney

PubMed Central

Park, Daeui; Kim, Byoung-Chul; Kim, Chul-Hong; Choi, Yeon Ja; Jeong, Hyoung Oh; Kim, Mi Eun; Lee, Jun Sik; Park, Min Hi; Chung, Ki Wung; Kim, Dae Hyun; Lee, Jaewon; Im, Dong-Soon; Yoon, Seokjoo; Lee, Sunghoon; Yu, Byung Pal; Bhak, Jong; Chung, Hae Young

2016-01-01

Age-related dysregulated inflammation plays an essential role as a major risk factor underlying the pathophysiological aging process. To better understand how inflammatory processes are related to aging at the molecular level, we sequenced the transcriptome of young and aged rat kidney using RNA-Seq to detect known genes, novel genes, and alternative splicing events that are differentially expressed. By comparing young (6 months of age) and old (25 months of age) rats, we detected 722 up-regulated genes and 111 down-regulated genes. In the aged rats, we found 32 novel genes and 107 alternatively spliced genes. Notably, 6.6% of the up-regulated genes were related to inflammation (P < 2.2 × 10−16, Fisher exact t-test); 15.6% were novel genes with functional protein domains (P = 1.4 × 10−5); and 6.5% were genes showing alternative splicing events (P = 3.3 × 10−4). Based on the results of pathway analysis, we detected the involvement of inflammation-related pathways such as cytokines (P = 4.4 × 10−16), which were found up-regulated in the aged rats. Furthermore, an up-regulated inflammatory gene analysis identified the involvement of transcription factors, such as STAT4, EGR1, and FOSL1, which regulate cancer as well as inflammation in aging processes. Thus, RNA changes in these pathways support their involvement in the pro-inflammatory status during aging. We propose that whole RNA-Seq is a useful tool to identify novel genes and alternative splicing events by documenting broadly implicated inflammation-related genes involved in aging processes. PMID:27153548

Wound Healing in Mac-1 Deficient Mice

DTIC Science & Technology

2017-05-01

36. Rosenkranz AR, Coxon A, Maurer M, Gurish MF, Austen KF, Friend DS, Galli SJ, Mayadas TN. Impaired mast cell development and innate immunity in Mac...genetically deficient mice. 3 INTRODUCTION Wound healing is a complex yet well-regulated process in which multiple resident cells ...recruited inflammatory cells , and stem cells interact to create an environment that supports the healing process. An optimal inflammatory response is a

CPEB1 modulates lipopolysaccharide-mediated iNOS induction in rat primary astrocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Ki Chan; Hyun Joo, So; Shin, Chan Young, E-mail: chanyshin@kku.ac.kr

2011-06-17

Highlights: {yields} Expression and phosphorylation of CPEB1 is increased by LPS stimulation in rat primary astrocytes. {yields} JNK regulates expression and phosphorylation of CPEB1 in reactive astrocytes. {yields} Down-regulation of CPEB1 using siRNA inhibits oxidative stress and iNOS induction by LPS stimulation. {yields} CPEB1 may play an important role in regulating inflammatory responses in reactive astrocytes induced by LPS. -- Abstract: Upon CNS damage, astrocytes undergo a series of biological changes including increased proliferation, production of inflammatory mediators and morphological changes, in a response collectively called reactive gliosis. This process is an essential part of the brains response to injury,more » yet much is unknown about the molecular mechanism(s) that induce these changes. In this study, we investigated the role of cytoplasmic polyadenylation element binding protein 1 (CPEB1) in the regulation of inflammatory responses in a model of reactive gliosis, lipopolysaccharide-stimulated astrocytes. CPEB1 is an mRNA-binding protein recently shown to be expressed in astrocytes that may play a role in astrocytes migration. After LPS stimulation, the expression and phosphorylation of CPEB1 was increased in rat primary astrocytes in a JNK-dependent process. siRNA-induced knockdown of CPEB1 expression inhibited the LPS-induced up-regulation of iNOS as well as NO and ROS production, a hallmark of immunological activation of astrocytes. The results from the study suggest that CPEB1 is actively involved in the regulation of inflammatory responses in astrocytes, which might provide new insights into the regulatory mechanism after brain injury.« less

Lysine Deacetylases and Regulated Glycolysis in Macrophages.

PubMed

Shakespear, Melanie R; Iyer, Abishek; Cheng, Catherine Youting; Das Gupta, Kaustav; Singhal, Amit; Fairlie, David P; Sweet, Matthew J

2018-06-01

Regulated cellular metabolism has emerged as a fundamental process controlling macrophage functions, but there is still much to uncover about the precise signaling mechanisms involved. Lysine acetylation regulates the activity, stability, and/or localization of metabolic enzymes, as well as inflammatory responses, in macrophages. Two protein families, the classical zinc-dependent histone deacetylases (HDACs) and the NAD-dependent HDACs (sirtuins, SIRTs), mediate lysine deacetylation. We describe here mechanisms by which classical HDACs and SIRTs directly regulate specific glycolytic enzymes, as well as evidence that links these protein deacetylases to the regulation of glycolysis-related genes. In these contexts, we discuss HDACs and SIRTs as key control points for regulating immunometabolism and inflammatory outputs from macrophages. Copyright © 2018 Elsevier Ltd. All rights reserved.

Expression and regulation of long noncoding RNAs during the osteogenic differentiation of periodontal ligament stem cells in the inflammatory microenvironment.

PubMed

Zhang, Qingbin; Chen, Li; Cui, Shiman; Li, Yan; Zhao, Qi; Cao, Wei; Lai, Shixiang; Yin, Sanjun; Zuo, Zhixiang; Ren, Jian

2017-10-25

Although long noncoding RNAs (lncRNAs) have been emerging as critical regulators in various tissues and biological processes, little is known about their expression and regulation during the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in inflammatory microenvironment. In this study, we have identified 63 lncRNAs that are not annotated in previous database. These novel lncRNAs were not randomly located in the genome but preferentially located near protein-coding genes related to particular functions and diseases, such as stem cell maintenance and differentiation, development disorders and inflammatory diseases. Moreover, we have identified 650 differentially expressed lncRNAs among different subsets of PDLSCs. Pathway enrichment analysis for neighboring protein-coding genes of these differentially expressed lncRNAs revealed stem cell differentiation related functions. Many of these differentially expressed lncRNAs function as competing endogenous RNAs that regulate protein-coding transcripts through competing shared miRNAs.

Innate Immune Regulations and Liver Ischemia Reperfusion Injury

PubMed Central

Lu, Ling; Zhou, Haoming; Ni, Ming; Wang, Xuehao; Busuttil, Ronald; Kupiec-Weglinski, Jerzy; Zhai, Yuan

2016-01-01

Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory, but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver IRI involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver IRI in patients. PMID:27861288

Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics

PubMed Central

Antoni, Michael H.; Lutgendorf, Susan K.; Blomberg, Bonnie; Carver, Charles S.; Lechner, Suzanne; Diaz, Alain; Stagl, Jamie; Arevalo, Jesusa M.G.; Cole, Steven W.

2011-01-01

Background Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a Cognitive-Behavioral Stress Management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat. Methods 199 women undergoing primary treatment of Stage 0–III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. 79 provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-, and 12-month follow-ups. Results Baseline negative affect was associated with > 50% differential expression of 201 leukocyte transcripts, including up-regulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by > 50% at follow-up (Group × Time interaction), including down-regulation of pro-inflammatory and metastasis-related genes and up-regulation of Type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of Interferon Response Factors and the Glucocorticoid Receptor (GR) as potential mediators of CBSM-induced transcriptional alterations. Conclusions In early stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related up-regulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes. PMID:22088795

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

PubMed Central

Irwin, Michael R; Opp, Mark R

2017-01-01

Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder. This review and overview provides an integrated understanding of the reciprocal relationships between sleep and the innate immune system and considers the role of sleep in the nocturnal regulation of the inflammatory biology dynamics; the impact of insomnia complaints, extremes of sleep duration, and experimental sleep deprivation on genomic, cellular, and systemic markers of inflammation; and the influence of sleep complaints and insomnia on inflammaging and molecular processes of cellular aging. Clinical implications of this research include discussion of the contribution of sleep disturbance to depression and especially inflammation-related depressive symptoms. Reciprocal action of inflammatory mediators on the homeostatic regulation of sleep continuity and sleep macrostructure, and the potential of interventions that target insomnia to reverse inflammation, are also reviewed. Together, interactions between sleep and inflammatory biology mechanisms underscore the implications of sleep disturbance for inflammatory disease risk, and provide a map to guide the development of treatments that modulate inflammation, improve sleep, and promote sleep health. PMID:27510422

Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.

PubMed

Tull, Samantha P; Yates, Clara M; Maskrey, Benjamin H; O'Donnell, Valerie B; Madden, Jackie; Grimble, Robert F; Calder, Philip C; Nash, Gerard B; Rainger, G Ed

2009-08-01

Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.

Tonic regulation of vascular permeability

PubMed Central

Curry, Fitz-Roy E.; Adamson, Roger H.

2014-01-01

Our major theme is that the layered structure of the endothelial barrier requires continuous activation of signaling pathways regulated by S1P and intracellular cAMP. These pathways modulate the adherens junction, continuity of tight junction strands, and the balance of synthesis and degradation of glycocalyx components. We evaluate recent evidence that baseline permeability is maintained by constant activity of mechanisms involving the small GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when activities of the small GTPases are reduced by low S1P supply or delivery. With inflammatory stimulus, increased permeability can be understood in part as the action of signaling to reduce Rap1 and Rac1 activation. With the hypothesis that microvessel permeability and selectivity under both normal and inflammatory conditions are regulated by mechanisms that are continuously active it follows that when S1P or intracellular cAMP are elevated at the time of inflammatory stimulus, they can buffer changes induced by inflammatory agents and maintain normal barrier stability. When endothelium is exposed to inflammatory conditions and subsequently exposed to elevated S1P or intracellular cAMP, the same processes restore the functional barrier by first reestablishing the adherens junction, then modulating tight junctions and glycocalyx. In more extreme inflammatory conditions, loss of the inhibitory actions of Rac1 dependent mechanisms may promote expression of more inflammatory endothelial phenotypes by contributing to the up-regulation of RhoA dependent contractile mechanisms and the sustained loss of surface glycocalyx allowing access of inflammatory cells to the endothelium. PMID:23374222

Molecular inflammation as an underlying mechanism of the aging process and age-related diseases.

PubMed

Chung, H Y; Lee, E K; Choi, Y J; Kim, J M; Kim, D H; Zou, Y; Kim, C H; Lee, J; Kim, H S; Kim, N D; Jung, J H; Yu, B P

2011-07-01

Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism's pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.

Resveratrol downregulates inflammatory pathway activated by lymphotoxin α (TNF-β) in articular chondrocytes: Comparison with TNF-α

PubMed Central

Buhrmann, Constanze; Popper, Bastian; Aggarwal, Bharat B.

2017-01-01

While Lymphotoxin α (TNF-β), a product of lymphocytes, is known to play a pivotal role in inflammatory joint environment, resveratrol has been shown to possess anti-inflammatory and chondroprotective effects via activation of the histondeacetylase Sirt1. Whether TNF-β induction of inflammatory pathways in primary human chondrocytes (PCH) can be modulated by resveratrol, was investigated. Monolayer and alginate cultures of PCH were treated with TNF-β, anti-TNF-β, nicotinamide (NAM), antisense oligonucleotides against Sirt1 (Sirt1-ASO) and/or resveratrol and co-cultured with T-lymphocytes. We found that resveratrol suppressed, similar to anti-TNF-β, TNF-β-induced increased adhesiveness in an inflammatory microenvironment of T-lymphocytes and PCH. In contrast, knockdown of Sirt1 by mRNA abolished the inhibitory effects of resveratrol on the TNF-β-induced adhesiveness, suggesting the essential role of this enzyme for resveratrol-mediated anti-inflammatory signaling. Similar results were obtained in PCH stimulated with TNF-α. Sirt1-ASO, NAM or TNF-β, similar to T-lymphocytes induced inflammatory microenvironment by down-regulation of cartilage-specific proteins, Sox9, Ki67 and enhanced NF-κB-regulated gene products involved in inflammatory and degradative processes in cartilage (MMP-9/-13, COX-2, caspase-3), NF-κB activation and its translocation to the nucleus. Moreover, resveratrol reversed the TNF-β-, NAM-, T-lymphocytes-induced up-regulation of various NF-κB-regulated gene products. Down-regulation of Sirt1 by mRNA interference abrogated the effect of resveratrol on TNF-β-induced effects. Ultrastructural and cell viability assay investigations revealed that resveratrol revoked TNF-β-induced dose-dependent degradative/apoptotic morphological changes, cell viability and proliferation in PCH. Taken together, suppression of TNF-β-induced inflammatory microenvironment in PCH by resveratrol/Sirt1 might be a novel therapeutic approach for targeting inflammation during rheumatoid arthritis. PMID:29095837

MicroRNA-155 facilitates skeletal muscle regeneration by balancing pro- and anti-inflammatory macrophages

PubMed Central

Nie, M; Liu, J; Yang, Q; Seok, H Y; Hu, X; Deng, Z-L; Wang, D-Z

2016-01-01

Skeletal muscle has remarkable regeneration capacity and regenerates in response to injury. Muscle regeneration largely relies on muscle stem cells called satellite cells. Satellite cells normally remain quiescent, but in response to injury or exercise they become activated and proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Interestingly, the inflammatory process following injury and the activation of the myogenic program are highly coordinated, with myeloid cells having a central role in modulating satellite cell activation and regeneration. Here, we show that genetic deletion of microRNA-155 (miR-155) in mice substantially delays muscle regeneration. Surprisingly, miR-155 does not appear to directly regulate the proliferation or differentiation of satellite cells. Instead, miR-155 is highly expressed in myeloid cells, is essential for appropriate activation of myeloid cells, and regulates the balance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages during skeletal muscle regeneration. Mechanistically, we found that miR-155 suppresses SOCS1, a negative regulator of the JAK-STAT signaling pathway, during the initial inflammatory response upon muscle injury. Our findings thus reveal a novel role of miR-155 in regulating initial immune responses during muscle regeneration and provide a novel miRNA target for improving muscle regeneration in degenerative muscle diseases. PMID:27277683

Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases.

PubMed

Waetzig, G H; Schreiber, S

2003-07-01

Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.

TUNING IMMUNE TOLERANCE WITH VASOACTIVE INTESTINAL PEPTIDE: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS

PubMed Central

POZO, DAVID; GONZALEZ-REY, ELENA; CHORNY, ALEJO; ANDERSON, PER; VARELA, NIEVES; DELGADO, MARIO

2007-01-01

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. PMID:17521775

Growth Hormone Resistance—Special Focus on Inflammatory Bowel Disease

PubMed Central

Soendergaard, Christoffer; Young, Jonathan A.; Kopchick, John J.

2017-01-01

Growth hormone (GH) plays major anabolic and catabolic roles in the body and is important for regulating several aspects of growth. During an inflammatory process, cells may develop a state of GH resistance during which their response to GH stimulation is limited. In this review, we will emphasize specific mechanisms governing the formation of GH resistance in the active phase of inflammatory bowel disease. The specific molecular effects mediated through individual inflammatory mediators and processes will be highlighted to provide an overview of the transcriptional, translational and post-translational inflammation-mediated impacts on the GH receptor (GHR) along with the impacts on GH-induced intracellular signaling. We also will review GH’s effects on mucosal healing and immune cells in the context of experimental colitis, human inflammatory bowel disease and in patients with short bowel syndrome. PMID:28486400

Neutrophil Apoptosis: Relevance to the Innate Immune Response and Inflammatory Disease

PubMed Central

Fox, Sarah; Leitch, Andrew E.; Duffin, Rodger; Haslett, Christopher; Rossi, Adriano G.

2010-01-01

Neutrophils are the most abundant cell type involved in the innate immune response. They are rapidly recruited to sites of injury or infection where they engulf and kill invading microorganisms. Neutrophil apoptosis, the process of programmed cell death that prevents the release of neutrophil histotoxic contents, is tightly regulated and limits the destructive capacity of neutrophil products to surrounding tissue. The subsequent recognition and phagocytosis of apoptotic cells by phagocytic cells such as macrophages is central to the successful resolution of an inflammatory response and it is increasingly apparent that the dying neutrophil itself exerts an anti-inflammatory effect through modulation of surrounding cell responses, particularly macrophage inflammatory cytokine release. Apoptosis may be delayed, induced or enhanced by micro-organisms dependent on their immune evasion strategies and the health of the host they encounter. There is now an established field of research aimed at understanding the regulation of apoptosis and its potential as a target for therapeutic intervention in inflammatory and infective diseases. This review focuses on the physiological regulation of neutrophil apoptosis with respect to the innate immune system and highlights recent advances in mechanistic understanding of apoptotic pathways and their therapeutic manipulation in appropriate and excessive innate immune responses. PMID:20375550

Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland

PubMed Central

Hewit, Kay D.; Pallas, Kenneth J.; Cairney, Claire J.; Lee, Kit M.; Hansell, Christopher A.; Stein, Torsten

2017-01-01

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2−/− mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes. PMID:27888192

Cold-Induced Browning Dynamically Alters the Expression Profiles of Inflammatory Adipokines with Tissue Specificity in Mice.

PubMed

Luo, Xiao; Jia, Ru; Zhang, Qiangling; Sun, Bo; Yan, Jianqun

2016-05-23

Cold exposure or β₃-adrenoceptor agonist treatment induces the adipose tissues remodeling, relevant for beige adipogenesis within white adipose tissue (WAT). It remains unclear whether this process influences inflammatory adipokines expression in adipose tissues. We determine the temporal profile of cold or β₃-adrenoceptor agonist (CL316,243)-induced changes in the expression of inflammatory adipokines in adipose tissues in mice or primary mice adipocytes. Male C57BL/6J mice at eight weeks old were exposed to 4 °C for 1-5 days. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous WAT (sWAT) and epididymal WAT (eWAT) were harvested for gene and protein expression analysis. In addition, cultured primary mice brown adipocyte (BA) and white adipocyte (WA) treated with or without CL316,243 were harvested for gene expression analysis. The inflammatory adipokines expressed significantly higher in WAT than BAT at baseline. They were rapidly changed in iBAT, while down-regulated in sWAT and up-regulated in eWAT during the cold acclimation. Upon CL316,243 treatment, detected inflammatory adipokines except Leptin were transiently increased in both BA and WA. Our in vivo and in vitro data demonstrate that the browning process alters the inflammatory adipokines expression in adipose tissues, which is acutely responded to in iBAT, dynamically decreased in sWAT whilst increased in eWAT for compensation.

Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma.

PubMed

Rao, Savita P; Ge, Xiao Na; Sriramarao, P

2017-01-01

Eosinophils are differentiated granulocytes that are recruited from the bone marrow to sites of inflammation via the vascular system. Allergic asthma is characterized by the presence of large numbers of eosinophils in the lungs and airways. Due to their capacity to rapidly release inflammatory mediators such as cytokines, chemokines, growth factors, and cytotoxic granule proteins upon stimulation, eosinophils play a critical role in pro-inflammatory processes in allergen-exposed lungs. Identifying key players and understanding the molecular mechanisms directing eosinophil trafficking and recruitment to inflamed airways is a key to developing therapeutic strategies to limit their influx. Recent studies have brought to light the important role of glycans and glycan binding proteins in regulating recruitment of eosinophils. In addition to the role of previously identified eosinophil- and endothelial-expressed adhesion molecules in mediating eosinophil trafficking and recruitment to the inflamed airways, studies have also indicated a role for galectins (galectin-3) in this process. Galectins are mammalian lectins expressed by various cell types including eosinophils. Intracellularly, they can regulate biological processes such as cell motility. Extracellularly, galectins interact with β-galactosides in cell surface-expressed glycans to regulate cellular responses like production of inflammatory mediators, cell adhesion, migration, and apoptosis. Eosinophils express galectins intracellularly or on the cell surface where they interact with cell surface glycoconjugate receptors. Depending on the type (galectin-1, -3, etc.) and location (extracellular or intracellular, endogenous or exogenously delivered), galectins differentially regulate eosinophil recruitment, activation, and apoptosis and thus exert a pro- or anti-inflammatory outcome. Here, we have reviewed information pertaining to galectins (galectin-1, -3 -9, and -10) that are expressed by eosinophils themselves and/or other cells that play a role in eosinophil recruitment and function in the context of allergic asthma and their potential use as disease biomarkers or therapeutic targets for immunomodulation.

Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state

PubMed Central

Zen, Ke; Guo, Yalan; Bian, Zhen; Lv, Zhiyuan; Zhu, Dihan; Ohnishi, Hiroshi; Matozaki, Takashi; Liu, Yuan

2018-01-01

Signal regulatory protein α (SIRPα), an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor, is an essential negative regulator of leukocyte inflammatory responses. Here we report that SIRPα cytoplasmic signalling ITIMs in neutrophils are cleaved during active inflammation and that the loss of SIRPα ITIMs enhances the polymorphonuclear leukocyte (PMN) inflammatory response. Using human leukocytes and two inflammatory models in mice, we show that the cleavage of SIRPα ITIMs in PMNs but not monocytes occurs at the post-acute stage of inflammation and correlates with increased PMN recruitment to inflammatory loci. Enhanced transmigration of PMNs and PMN-associated tissue damage are confirmed in mutant mice expressing SIRPα but lacking the ITIMs. Moreover, the loss of SIRPα ITIMs in PMNs during colitis is blocked by an anti-interleukin-17 (IL-17) antibody. These results demonstrate a SIRPα-based mechanism that dynamically regulates PMN inflammatory responses by generating a CD47-binding but non-signalling SIRPα ‘decoy’. PMID:24026300

Role of milk fat globule-epidermal growth factor 8 in osteoimmunology

PubMed Central

Sinningen, Kathrin; Thiele, Sylvia; Hofbauer, Lorenz C; Rauner, Martina

2016-01-01

Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that is abundantly expressed in various tissues and has a pivotal role in the phagocytic clearance of apoptotic cells. However, MFG-E8 has also gained significant attention because of its wide range of functions in autoimmunity, inflammation and tissue homeostasis. More recently, MFG-E8 has been identified as a critical regulator of bone homeostasis, being expressed in both, osteoblasts and osteoclasts. In addition, it was shown that MFG-E8 fulfils an active role in modulating inflammatory processes, suggesting an anti-inflammatory role of MFG-E8 and proposing it as a novel therapeutic target for inflammatory diseases. This concise review focusses on the expression and regulation of MFG-E8 in the context of inflammatory bone diseases, highlights its role in the pathophysiology of osteoimmune diseases and discusses the therapeutic potential of MFG-E8. PMID:27579162

[Persistence of chronic inflammatory responses, role in the development of chronic pancreatitis, obesity and pancreatic cancer].

PubMed

Khristich, T N

2014-11-01

The purpose of the review--to analyze the basic data of the role of chronic low-intensity inflammatory response as general biological process in the development and progression of chronic pancreatitis, obesity, and pancreatic cancer. Highlighted evidence from epidemiological studies showing that chronic pancreatitis and obesity are independent risk factors for pancreatic cancer, regardless of diabetes. Studied role of adipokines as Cytokines regulating of immune inflammatory response. Draws attention to the staging of pancreatic cancer in obesity.

Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

PubMed Central

Smith, Judith A.

2018-01-01

Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defense against pathogens, but when aberrantly produced, may also drive pathologic inflammation. The UPR influences cytokine production on multiple levels, from stimulation of pattern recognition receptors, to modulation of inflammatory signaling pathways, and the regulation of cytokine transcription factors. This review will focus on the mechanisms underlying cytokine regulation by the UPR, and the repercussions of this relationship for infection and autoimmune/autoinflammatory diseases. Interrogation of viral and bacterial infections has revealed increasing numbers of examples where pathogens induce or modulate the UPR and implicated UPR-modulated cytokines in host response. The flip side of this coin, the UPR/ER stress responses have been increasingly recognized in a variety of autoimmune and inflammatory diseases. Examples include monogenic disorders of ER function, diseases linked to misfolding protein (HLA-B27 and spondyloarthritis), diseases directly implicating UPR and autophagy genes (inflammatory bowel disease), and autoimmune diseases targeting highly secretory cells (e.g., diabetes). Given the burgeoning interest in pharmacologically targeting the UPR, greater discernment is needed regarding how the UPR regulates cytokine production during specific infections and autoimmune processes, and the relative place of this interaction in pathogenesis. PMID:29556237

RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis.

PubMed

Miller, Christine H; Smith, Sinead M; Elguindy, Mahmoud; Zhang, Tuo; Xiang, Jenny Z; Hu, Xiaoyu; Ivashkiv, Lionel B; Zhao, Baohong

2016-06-15

Increased osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α-induced osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow-derived macrophages/osteoclast precursors during inflammatory osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced osteoclastogenesis program induced by TNF-α in RBP-J-deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte-induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α-mediated osteoclastogenesis. Thus, RBP-J-regulated miR-182 promotes TNF-α-induced osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α-induced osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits osteoclastogenesis and suggest that targeting of the newly described RBP-J-miR-182-Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone resorption. Copyright © 2016 by The American Association of Immunologists, Inc.

Transcriptome analysis reveals mucin 4 to be highly associated with periodontitis and identifies pleckstrin as a link to systemic diseases

PubMed Central

Lundmark, Anna; Davanian, Haleh; Båge, Tove; Johannsen, Gunnar; Koro, Catalin; Lundeberg, Joakim; Yucel-Lindberg, Tülay

2015-01-01

The multifactorial chronic inflammatory disease periodontitis, which is characterized by destruction of tooth-supporting tissues, has also been implicated as a risk factor for various systemic diseases. Although periodontitis has been studied extensively, neither disease-specific biomarkers nor therapeutic targets have been identified, nor its link with systemic diseases. Here, we analyzed the global transcriptome of periodontitis and compared its gene expression profile with those of other inflammatory conditions, including cardiovascular disease (CVD), rheumatoid arthritis (RA), and ulcerative colitis (UC). Gingival biopsies from 62 patients with periodontitis and 62 healthy subjects were subjected to RNA sequencing. The up-regulated genes in periodontitis were related to inflammation, wounding and defense response, and apoptosis, whereas down-regulated genes were related to extracellular matrix organization and structural support. The most highly up-regulated gene was mucin 4 (MUC4), and its protein product was confirmed to be over-expressed in periodontitis. When comparing the expression profile of periodontitis with other inflammatory diseases, several gene ontology categories, including inflammatory response, cell death, cell motion, and homeostatic processes, were identified as common to all diseases. Only one gene, pleckstrin (PLEK), was significantly overexpressed in periodontitis, CVD, RA, and UC, implicating this gene as an important networking link between these chronic inflammatory diseases. PMID:26686060

The regulation of Jmjd3 upon the expression of NF-κB downstream inflammatory genes in LPS activated vascular endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Shaoqing; Graduate School of Medicine, Nanchang University, Nanchang; Chen, Xia

Inflammatory mediators and adhesion molecules have been implicated in a variety of diseases including atherosclerosis. As both the mediator-releasing and targeted cells, vascular endothelial cells play key role in pathological processes. NF-κB signaling regulates a cluster of inflammatory factors in LPS-activated vascular endothelial cells but the underlying mechanisms remain largely unknown. Here, we investigated the epigenetic regulation of LPS upon the expression of inflammatory mediators and adhesion molecules. We found that LPS treatment promoted jmjd3 expression, enhanced Jmjd3 nuclear accumulation in human vascular endothelial cells. In addition, LPS enhanced the demethylation of H3K27me3, a specific substrate of Jmjd3. LPS treatmentmore » recruited Jmjd3 and NF-κB to the promoter region of target genes, suggesting Jmjd3 synergizes with NF-κB to activate the expression of target genes. We further found that Jmjd3 attenuated the methylation status in promoter region of target genes, culminating in target gene expression. Our findings unveil epigenetic regulations of LPS upon NF-κB pathway and identify Jmjd3 as a critical modulator of NF-κB pathway and potential therapeutic target for NF-κB related diseases including atherosclerosis.« less

Inflammasome and Autophagy Regulation: A Two-way Street

PubMed Central

Qian, Sun; Fan, Jie; Billiar, Timothy R; Scott, Melanie J

2017-01-01

Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer’s disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases. PMID:28741645

A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice.

PubMed

Porter, John D; Khanna, Sangeeta; Kaminski, Henry J; Rao, J Sunil; Merriam, Anita P; Richmonds, Chelliah R; Leahy, Patrick; Li, Jingjin; Guo, Wei; Andrade, Francisco H

2002-02-01

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.

Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms.

PubMed Central

Balding, Joanna; Livingstone, Wendy J; Conroy, Judith; Mynett-Johnson, Lesley; Weir, Donald G; Mahmud, Nasir; Smith, Owen P

2004-01-01

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear. PMID:15223609

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.

PubMed

Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana; Koudelka, Adolf; Rudolph, Tanja K; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

2016-11-01

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Rab7-a novel redox target that modulates inflammatory pain processing.

PubMed

Kallenborn-Gerhardt, Wiebke; Möser, Christine V; Lorenz, Jana E; Steger, Mirco; Heidler, Juliana; Scheving, Reynir; Petersen, Jonas; Kennel, Lea; Flauaus, Cathrin; Lu, Ruirui; Edinger, Aimee L; Tegeder, Irmgard; Geisslinger, Gerd; Heide, Heinrich; Wittig, Ilka; Schmidtko, Achim

2017-07-01

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.

Reactive Oxygen Species in Metabolic and Inflammatory Signaling.

PubMed

Forrester, Steven J; Kikuchi, Daniel S; Hernandes, Marina S; Xu, Qian; Griendling, Kathy K

2018-03-16

Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases. © 2018 American Heart Association, Inc.

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice

PubMed Central

Shin, Jihyun; Yang, Soo Jin

2016-01-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1-α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1. PMID:28211759

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice.

PubMed

Shin, Jihyun; Yang, Soo Jin; Lim, Yunsook

2017-03-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1- α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1.

Biological pathways involved in the development of inflammatory bowel disease.

PubMed

Zemljic, Mateja; Pejkovic, Bozena; Krajnc, Ivan; Lipovsek, Saska

2014-10-01

Apoptosis, autophagy and necrosis are three distinct functional types of the mammalian cell death network. All of them are characterized by a number of cell's morphological changes. The inappropriate induction of cell death is involved in the pathogenesis of a number of diseases.Pathogenesis of inflammatory bowel diseases (ulcerative colitis, Crohn's disease) includes an abnormal immunological response to disturbed intestinal microflora. One of the most important reason in pathogenesis of chronic inflammatory disease and subsequent multiple organ pathology is a barrier function of the gut, regulating cellular viability. Recent findings have begun to explain the mechanisms by which intestinal epithelial cells are able to survive in such an environment and how loss of normal regulatory processes may lead to inflammatory bowel disease (IBD).This review focuses on the regulation of biological pathways in development and homeostasis in IBD. Better understanding of the physiological functions of biological pathways and their influence on inflammation, immunity, and barrier function will simplify our expertice of homeostasis in the gastrointestinal tract and in upgrading diagnosis and treatment.

Visualization of T Cell-Regulated Monocyte Clusters Mediating Keratinocyte Death in Acquired Cutaneous Immunity.

PubMed

Liu, Zheng; Yang, Fei; Zheng, Hao; Fan, Zhan; Qiao, Sha; Liu, Lei; Tao, Juan; Luo, Qingming; Zhang, Zhihong

2018-06-01

It remains unclear how monocytes are mobilized to amplify inflammatory reactions in T cell-mediated adaptive immunity. Here, we investigate dynamic cellular events in the cascade of inflammatory responses through intravital imaging of a multicolor-labeled murine contact hypersensitivity model. We found that monocytes formed clusters around hair follicles in the contact hypersensitivity model. In this process, effector T cells encountered dendritic cells under regions of monocyte clusters and secreted IFN-γ, which mobilizes CCR2-dependent monocyte interstitial migration and CXCR2-dependent monocyte cluster formation. We showed that hair follicles shaped the inflammatory microenvironment for communication among the monocytes, keratinocytes, and effector T cells. After disrupting the T cell-mobilized monocyte clusters through CXCR2 antagonization, monocyte activation and keratinocyte apoptosis were significantly inhibited. Our study provides a new perspective on effector T cell-regulated monocyte behavior, which amplifies the inflammatory reaction in acquired cutaneous immunity. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Epigenetic regulation in dental pulp inflammation

PubMed Central

Hui, T; Wang, C; Chen, D; Zheng, L; Huang, D; Ye, L

2016-01-01

Dental caries, trauma, and other possible factors could lead to injury of the dental pulp. Dental infection could result in immune and inflammatory responses mediated by molecular and cellular events and tissue breakdown. The inflammatory response of dental pulp could be regulated by genetic and epigenetic events. Epigenetic modifications play a fundamental role in gene expression. The epigenetic events might play critical roles in the inflammatory process of dental pulp injury. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Infections and other environmental factors have profound effects on epigenetic modifications and trigger diseases. Despite growing evidences of literatures addressing the role of epigenetics in the field of medicine and biology, very little is known about the epigenetic pathways involved in dental pulp inflammation. This review summarized the current knowledge about epigenetic mechanisms during dental pulp inflammation. Progress in studies of epigenetic alterations during inflammatory response would provide opportunities for the development of efficient medications of epigenetic therapy for pulpitis. PMID:26901577

Fluocinolone acetonide partially restores the mineralization of LPS-stimulated dental pulp cells through inhibition of NF-κB pathway and activation of AP-1 pathway

PubMed Central

Liu, Zhongning; Jiang, Ting; Wang, Xinzhi; Wang, Yixiang

2013-01-01

BACKGROUND AND PURPOSE Fluocinolone acetonide (FA) is commonly used as a steroidal anti-inflammatory drug. We recently found that in dental pulp cells (DPCs) FA has osteo-/odonto-inductive as well as anti-inflammatory effects. However, the mechanism by which FA induces these effects in DPCs is poorly understood. EXPERIMENTAL APPROACH The effect of FA on the mineralization of DPCs during inflammatory conditions and the underlying mechanism were investigated by real-time PCR, Western blot, EMSA, histochemical staining, immunostaining and pathway blockade assays. KEY RESULTS FA significantly inhibited the inflammatory response in LPS-treated DPCs not only by down-regulating the expression of pro–inflammation-related genes, but also by up-regulating the expression of the anti-inflammatory gene PPAR-γ and mineralization-related genes. Moreover, histochemical staining and immunostaining showed that FA could partially restore the expressions of alkaline phosphatase, osteocalcin and dentin sialophosphoprotein (DSPP) and mineralization in LPS-stimulated DPCs. Real-time PCR and Western blot analysis revealed that FA up-regulated DSPP and runt-related transcription factor 2 expression by inhibiting the expression of phosphorylated-NF-κB P65 and activating activator protein-1 (AP-1) (p-c-Jun and Fra-1). These results were further confirmed through EMSA, by detection of NF-κB DNA-binding activity and pathway blockade assays using a NF-κB pathway inhibitor, AP-1 pathway inhibitor and glucocorticoid receptor antagonist. CONCLUSIONS AND IMPLICATIONS Inflammation induced by LPS suppresses the mineralization process in DPCs. FA partially restored this osteo-/odonto-genesis process in LPS-treated DPCs and had an anti-inflammatory effect through inhibition of the NF-κB pathway and activation of the AP-1 pathway. Hence, FA is a potential new treatment for inflammation-associated bone/teeth diseases. PMID:24024985

PUFA diets alter the microRNA expression profiles in an inflammation rat model

PubMed Central

ZHENG, ZHENG; GE, YINLIN; ZHANG, JINYU; XUE, MEILAN; LI, QUAN; LIN, DONGLIANG; MA, WENHUI

2015-01-01

Omega-3 and -6 polyunsaturated fatty acids (PUFAs) can directly or indirectly regulate immune homeostasis via inflammatory pathways, and components of these pathways are crucial targets of microRNAs (miRNAs). However, no study has examined the changes in the miRNA transcriptome during PUFA-regulated inflammatory processes. Here, we established PUFA diet-induced autoimmune-prone (AP) and autoimmune-averse (AA) rat models, and studied their physical characteristics and immune status. Additionally, miRNA expression patterns in the rat models were compared using microarray assays and bioinformatic methods. A total of 54 miRNAs were differentially expressed in common between the AP and the AA rats, and the changes in rno-miR-19b-3p, -146b-5p and -183-5p expression were validated using stem-loop reverse transcription-quantitative polymerase chain reaction. To better understand the mechanisms underlying PUFA-regulated miRNA changes during inflammation, computational algorithms and biological databases were used to identify the target genes of the three validated miRNAs. Furthermore, Gene Ontology (GO) term annotation and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in inflammatory pathways. The predicted PUFA-regulated inflammatory pathways included the Toll-like receptor (TLR), T cell receptor (TCR), NOD-like receptor (NLR), RIG-I-like receptor (RLR), mitogen-activated protein kinase (MAPK) and the transforming growth factor-β (TGF-β) pathway. This study is the first report, to the best of our knowledge, on in vivo comparative profiling of miRNA transcriptomes in PUFA diet-induced inflammatory rat models using a microarray approach. The results provide a useful resource for future investigation of the role of PUFA-regulated miRNAs in immune homeostasis. PMID:25672643

Molecular Mechanisms and Pathways as Targets for Cancer Prevention and Progression with Dietary Compounds.

PubMed

Nosrati, Nagisa; Bakovic, Marica; Paliyath, Gopinadhan

2017-09-25

A unique feature of bioactive food ingredients is their broad antioxidant function. Antioxidants having a wide spectrum of chemical structure and activity beyond basic nutrition; display different health benefits by the prevention and progression of chronic diseases. Functional food components are capable of enhancing the natural antioxidant defense system by scavenging reactive oxygen and nitrogen species, protecting and repairing DNA damage, as well as modulating the signal transduction pathways and gene expression. Major pathways affected by bioactive food ingredients include the pro-inflammatory pathways regulated by nuclear factor kappa B (NF-κB), as well as those associated with cytokines and chemokines. The present review summarizes the importance of plant bioactives and their roles in the regulation of inflammatory pathways. Bioactives influence several physiological processes such as gene expression, cell cycle regulation, cell proliferation, cell migration, etc., resulting in cancer prevention. Cancer initiation is associated with changes in metabolic pathways such as glucose metabolism, and the effect of bioactives in normalizing this process has been provided. Initiation and progression of inflammatory bowel diseases (IBD) which increase the chances of developing of colorectal cancers can be downregulated by plant bioactives. Several aspects of the potential roles of microRNAs and epigenetic modifications in the development of cancers have also been presented.

Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis.

PubMed

Cavaco, Sofia; Viegas, Carla S B; Rafael, Marta S; Ramos, Acácio; Magalhães, Joana; Blanco, Francisco J; Vermeer, Cees; Simes, Dina C

2016-03-01

Osteoarthritis (OA) is a whole-joint disease characterized by articular cartilage loss, tissue inflammation, abnormal bone formation and extracellular matrix (ECM) mineralization. Disease-modifying treatments are not yet available and a better understanding of osteoarthritis pathophysiology should lead to the discovery of more effective treatments. Gla-rich protein (GRP) has been proposed to act as a mineralization inhibitor and was recently shown to be associated with OA in vivo. Here, we further investigated the association of GRP with OA mineralization-inflammation processes. Using a synoviocyte and chondrocyte OA cell system, we showed that GRP expression was up-regulated following cell differentiation throughout ECM calcification, and that inflammatory stimulation with IL-1β results in an increased expression of COX2 and MMP13 and up-regulation of GRP. Importantly, while treatment of articular cells with γ-carboxylated GRP inhibited ECM calcification, treatment with either GRP or GRP-coated basic calcium phosphate (BCP) crystals resulted in the down-regulation of inflammatory cytokines and mediators of inflammation, independently of its γ-carboxylation status. Our results strengthen the calcification inhibitory function of GRP and strongly suggest GRP as a novel anti-inflammatory agent, with potential beneficial effects on the main processes responsible for osteoarthritis progression. In conclusion, GRP is a strong candidate target to develop new therapeutic approaches.

The roles of special proresolving mediators in pain relief.

PubMed

Zhang, Lan-Yu; Jia, Ming-Rui; Sun, Tao

2018-02-08

The resolution of acute inflammation, once thought to be a passive process, is now recognized as an active one. The productions of endogenous special proresolving mediators (SPMs) are involved in this process. SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated from ω-6 arachidonic acid or ω-3 poly-unsaturated fatty acids during the resolution phase of acute inflammation. They have potent anti-inflammatory and proresolving actions in various inflammatory disorders. Due to the potent proresolving and anti-inflammatory effects, SPMs are also used for pain relief. This review focuses on the mechanisms by which SPMs act on their respective G-protein-coupled receptors in immune cells and nerve cells to normalize pain via regulating inflammatory mediators, transient receptor potential ion channels, and central sensitization. SPMs may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation.

Endocellular regulation by free radicals and hydrogen peroxide: key determinants of the inflammatory response.

PubMed

Vitetta, Luis; Linnane, Anthony W

2014-04-01

The formations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been considered as major contributors to the dysregulation of the inflammatory response. Reactive oxygen species and RNS productions often are reported to be associated with the development of chronic diseases and acceleration of the aging process. Mechanistically, this association has linked the phenomena of oxidative stress with the occurrence of random deleterious modifications of macromolecules with progressive development of pro-inflammatory conditions promoting age-associated systemic diseases. On the contrary the so-called random modification of macromolecules is incorrect rather ROS and RNS are molecular regulators (second messengers) and not universal toxins whose overproduction should be annulled by antioxidants. We have previously reviewed the physiological role of superoxide anion (and hydrogen peroxide) and nitric oxide (and peroxynitrite) and concluded that these reactive molecular species behave as pro-oxidant second messengers. Reactive oxygen species and RNS are produced at specific cellular locations and are essential for both the normal physiological function of the metabolome and the regulated inflammatory response. This brings into question the whole concept of the orally administering of antioxidant molecular species to down-regulate or abrogate an overproduction of free radical activity. There are no human clinical trials that demonstrate that small molecules, the so-called antioxidants (e.g., vitamins C, vitamin E and beta-carotene), confer a favorable clinical outcome of long-lasting control of inflammation.

Cryotherapy Reduces Inflammatory Response Without Altering Muscle Regeneration Process and Extracellular Matrix Remodeling of Rat Muscle.

PubMed

Vieira Ramos, Gracielle; Pinheiro, Clara Maria; Messa, Sabrina Peviani; Delfino, Gabriel Borges; Marqueti, Rita de Cássia; Salvini, Tania de Fátima; Durigan, Joao Luiz Quagliotti

2016-01-04

The application of cryotherapy is widely used in sports medicine today. Cooling could minimize secondary hypoxic injury through the reduction of cellular metabolism and injury area. Conflicting results have also suggested cryotherapy could delay and impair the regeneration process. There are no definitive findings about the effects of cryotherapy on the process of muscle regeneration. The aim of the present study was to evaluate the effects of a clinical-like cryotherapy on inflammation, regeneration and extracellular matrix (ECM) remodeling on the Tibialis anterior (TA) muscle of rats 3, 7 and 14 days post-injury. It was observed that the intermittent application of cryotherapy (three 30-minute sessions, every 2 h) in the first 48 h post-injury decreased inflammatory processes (mRNA levels of TNF-α, NF-κB, TGF-β and MMP-9 and macrophage percentage). Cryotherapy did not alter regeneration markers such as injury area, desmin and Myod expression. Despite regulating Collagen I and III and their growth factors, cryotherapy did not alter collagen deposition. In summary, clinical-like cryotherapy reduces the inflammatory process through the decrease of macrophage infiltration and the accumulation of the inflammatory key markers without influencing muscle injury area and ECM remodeling.

CHARACTERIZATION OF INFLAMMATORY GENE EXPRESSION AND GALECTIN-3 FUNCTION AFTER SPINAL CORD INJURY IN MICE

PubMed Central

Pajoohesh-Ganji, Ahdeah; Knoblach, Susan M.; Faden, Alan I.; Byrnes, Kimberly R.

2012-01-01

Inflammation has long been implicated in secondary tissue damage after spinal cord injury (SCI). Our previous studies of inflammatory gene expression in rats after SCI revealed two temporally correlated clusters: the first was expressed early after injury and the second was up-regulated later, with peak expression at 1–2 weeks and persistent up-regulation through 6 months. To further address the role of inflammation after SCI, we examined inflammatory genes in a second species, mice, through 28 days after SCI. Using anchor gene clustering analysis, we found similar expression patterns for both the acute and chronic gene clusters previously identified after rat SCI. The acute group returned to normal expression levels by 7 days post-injury. The chronic group, which included C1qB, p22phox and galectin-3, showed peak expression at 7 days and remained up-regulated through 28 days. Immunohistochemistry and western blot analysis showed that the protein expression of these genes was consistent with the mRNA expression. Further exploration of the role of one of these genes, galectin-3, suggests that galectin-3 may contribute to secondary injury. In summary, our findings extend our prior gene profiling data by demonstrating the chronic expression of a cluster of microglial associated inflammatory genes after SCI in mice. Moreover, by demonstrating that inhibition of one such factor improves recovery, the findings suggest that such chronic up-regulation of inflammatory processes may contribute to secondary tissue damage after SCI, and that there may be a broader therapeutic window for neuroprotection than generally accepted. PMID:22884909

Fostering Inflammatory Bowel Disease: Sphingolipid Strategies to Join Forces

PubMed Central

Abdel Hadi, Loubna; Di Vito, Clara; Riboni, Laura

2016-01-01

Complex sphingolipids are essential structural components of intestinal membranes, providing protection and integrity to the intestinal mucosa and regulating intestinal absorption processes. The role of sphingolipid signaling has been established in numerous cellular events, including intestinal cell survival, growth, differentiation, and apoptosis. A significant body of knowledge demonstrates that intestinal sphingolipids play a crucial role, as such and through their signaling pathways, in immunity and inflammatory disorders. In this review, we report on and discuss the current knowledge on the metabolism, signaling, and functional implications of sphingolipids in inflammatory bowel disease (IBD), focusing on the different aspects of sphingolipid actions on inflammatory responses and on the potential of sphingolipid-targeted molecules as anti-IBD therapeutic agents. PMID:26880864

Brazilian Red Propolis Attenuates Inflammatory Signaling Cascade in LPS-Activated Macrophages

PubMed Central

Bueno-Silva, Bruno; Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Alencar, Severino M.; Rosalen, Pedro L.; Mayer, Marcia P. A.

2015-01-01

Although previous studies suggested an anti-inflammatory property of Brazilian red propolis (BRP), the mechanisms involved in the anti-inflammatory effects of BRP and its activity on macrophages were still not elucidated. This study aimed to evaluate whether BRP attenuates the inflammatory effect of LPS on macrophages and to investigate its underlying mechanisms. BRP was added to RAW 264.7 murine macrophages after activation with LPS. NO production, cell viability, cytokines profile were evaluated. Activation of inflammatory signaling pathways and macrophage polarization were determined by RT-qPCR and Western blot. BRP at 50 μg/ml inhibited NO production by 78% without affecting cell viability. Cd80 and Cd86 were upregulated whereas mrc1 was down regulated by BRP indicating macrophage polarization at M1. BRP attenuated the production of pro-inflammatory mediators IL-12, GM-CSF, IFN-Ɣ, IL-1β in cell supernatants although levels of TNF- α and IL-6 were slightly increased after BRP treatment. Levels of IL-4, IL-10 and TGF-β were also reduced by BRP. BRP significantly reduced the up-regulation promoted by LPS of transcription of genes in inflammatory signaling (Pdk1, Pak1, Nfkb1, Mtcp1, Gsk3b, Fos and Elk1) and of Il1β and Il1f9 (fold-change rate > 5), which were further confirmed by the inhibition of NF-κB and MAPK signaling pathways. Furthermore, the upstream adaptor MyD88 adaptor-like (Mal), also known as TIRAP, involved in TLR2 and TLR4 signaling, was down- regulated in BRP treated LPS-activated macrophages. Given that BRP inhibited multiple signaling pathways in macrophages involved in the inflammatory process activated by LPS, our data indicated that BRP is a noteworthy food-source for the discovery of new bioactive compounds and a potential candidate to attenuate exhacerbated inflammatory diseases. PMID:26660901

Integrating microRNAs into a system biology approach to acute lung injury.

PubMed

Zhou, Tong; Garcia, Joe G N; Zhang, Wei

2011-04-01

Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and nongenetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Because gene expression is an intermediate phenotype that resides between the DNA sequence variation and the higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks potentially could enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. MicroRNAs (miRNAs) have emerged as a novel class of gene regulators that play critical roles in complex diseases including ALI. Comparisons of global miRNA profiles in animal models of ALI and VILI identified several miRNAs (eg, miR-146a and miR-155) previously implicated in immune response and inflammatory pathways. Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. Although this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well as environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease. Copyright © 2011 Mosby, Inc. All rights reserved.

Receptor binding sites for substance P in surgical specimens obtained from patients with ulcerative colitis and Crohn disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mantyh, C.R.; Gates, T.S.; Zimmerman, R.P.

1988-05-01

Several lines of evidence indicate that tachykinin neuropeptides (substance P (SP), substance K (SK), and neuromedin K (NK)) play a role in regulating the inflammatory and immune responses. To test this hypothesis in a human inflammatory disease, quantitative receptor autoradiography was used to examine possible abnormalities in tachykinin binding sites in surgical specimens from patients with inflammatory bowel disease. In all cases, specimens were processed for quantitative receptor autoradiography by using /sup 125/I-labeled Bolton-Hunter conjugates of NK, SK, and SP. In colon tissue obtained from ulcerative colitis and Crohn disease patients, very high concentrations of SP receptor binding sites aremore » expressed by arterioles and venules located in the submucosa, muscalairs mucosa, external circular muscle, external longitudinal muscle, and serosa, in contrast to control patients. These results demonstrate that receptor binding sites for SP, but not SK or NK, are ectopically expressed in high concentrations by cells involved in mediating inflammatory and immune responses. These data suggest that SP may be involved in the pathophysiology of inflammatory bowel disease and might provide some insight into the interaction between the nervous system and the regulation of inflammation and the immune response in human inflammatory disease.« less

Marine Diterpenoids as Potential Anti-Inflammatory Agents

PubMed Central

González, Yisett; Torres-Mendoza, Daniel; Jones, Gillian E.; Fernandez, Patricia L.

2015-01-01

The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules. PMID:26538822

Resveratrol counteracts lipopolysaccharide-mediated microglial inflammation by modulating a SOCS-1 dependent signaling pathway.

PubMed

Dragone, Teresa; Cianciulli, Antonia; Calvello, Rosa; Porro, Chiara; Trotta, Teresa; Panaro, Maria Antonietta

2014-09-01

Brain damage or exposure to inflammatory agents provokes the activation of microglia and secretion of pro-inflammatory and neurotoxic mediators responsible for neuronal loss. Several lines of evidence show that resveratrol, a natural non-flavonoid polyphenol, may exert a neuroprotective action in neurodegenerative diseases. Suppressor of cytokine signaling (SOCS) proteins are a family of eight members expressed by immune cells and the central nervous system (CNS) cells, that regulate immune processes within the CNS, including microglia activation. We demonstrate that resveratrol had anti-inflammatory effects in murine N13 microglial cells stimulated with lipopolysaccharide (LPS), through up-regulating SOCS-1 expression. Interestingly, in SOCS-1-silenced cells resveratrol failed to play a protective role after LPS treatment. Our data demonstrate that resveratrol can impair microglia activation by activating a SOCS-1 mediated signaling pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

PubMed Central

Jope, Richard S.; Yuskaitis, Christopher J.; Beurel, Eléonore

2007-01-01

Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions. PMID:16944320

The longitudinal effects of emotion regulation on physical and psychological health: A latent growth analysis exploring the role of cognitive fusion in inflammatory bowel disease.

PubMed

Trindade, Inês A; Ferreira, Cláudia; Pinto-Gouveia, José

2018-02-01

This study thus aims to test differences between patients with inflammatory bowel disease (IBD) regarding IBD symptomatology, cognitive fusion, and psychological and physical health, as well as to explore whether the maladaptive emotion regulation process of cognitive fusion longitudinally impacts on the baseline and evolution of these outcomes over a period of 18 months. Participants include 116 IBD patients with a mean age of 36.76 (SD = 11.39) of both genders (69.83% females) that completed the self-report measures of interest in three different times, equally spaced 9 months apart, over a period of 18 months. Latent growth curve models were conducted using structural equation modelling to estimate the growth trajectory of the variables in study. Inflammatory bowel disease symptomatology and cognitive fusion's levels were negatively associated with psychological health and physical health's baseline levels. Furthermore, IBD symptomatology did not influence the growth of psychological health, while cognitive fusion did (β = .30, p = .007). The same result was found for physical health (β = .26, p = .024). These findings indicate that individuals with higher levels of cognitive fusion present lower levels of psychological health and physical health that tend to further decrease over the time through the effects of this maladaptive emotion regulation process. This study implies that it is of crucial importance to include psychotherapeutic interventions in the health care of patients with IBD. If successful, these interventions could represent decreases in the cost of IBD treatment and in the use of drugs with adverse side effects, in addition to improving patients' mental health and quality of life. Further implications for clinical and research work are discussed. Statement of contribution What is already known on this subject? Research has demonstrated the impact of emotion regulation on both physical and mental health. Nevertheless, the longitudinal effects of the specific emotion regulation process of cognitive fusion on physical and psychological health have never been explored. Additionally, no study has yet examined the causal role of emotion regulation in evolution of physical health in inflammatory bowel disease (IBD). What does this study add? Cognitive fusion longitudinally impacted on IBD patients' physical and mental health. These variables were measured over a period of 18 months. Treatment for IBD should include interventions aiming to diminish maladaptive emotion regulation. © 2017 The British Psychological Society.

ENGULFMENT OF APOPTOTIC CELLS BY MACROPHAGES: A ROLE OF MICRO-RNA-21 IN THE RESOLUTION OF WOUND INFLAMMATION1

PubMed Central

Das, Amitava; Ganesh, Kasturi; Khanna, Savita; Sen, Chandan K.; Roy, Sashwati

2014-01-01

SUMMARY At an injury-site, efficient clearance of apoptotic cells by wound macrophages or efferocytosis is a pre-requisite for the timely resolution of inflammation. Emerging evidence indicates that miR-21 may regulate the inflammatory response. In this work, we sought to elucidate the significance of miR-21 in the regulation of efferocytosis mediated suppression of innate immune response, a key process implicated in resolving inflammation following injury. An increased expression of inducible miR-21 was noted in post-efferocytotic peripheral blood monocyte-derived macrophages (MDM). Such induction of miR-21 was associated with silencing of its target genes PTEN and PDCD4. Successful efferocytosis of apoptotic cells by MDM resulted in the suppression of LPS-induced NF-κB activation and TNFα expression. Interestingly, bolstering of miR-21 levels alone using miR mimic resulted in significant suppression of LPS-induced TNFα expression and NFκB activation. We report that efferocytosis-induced miR-21, by silencing PTEN and GSK3β, tempers LPS-induced inflammatory response. Macrophage efferocytosis is known to trigger the release of anti-inflammatory cytokine IL-10. This study demonstrates that following successful efferocytosis, miR-21 induction in macrophages silence PDCD4 favoring cJun-AP1 activity which in turn results in elevated production of anti-inflammatory IL-10. In summary, this work provides direct evidence implicating miRNA in the process of turning-on an anti-inflammatory phenotype in the post-efferocytotic macrophage. Elevated macrophage miR-21 promotes efferocytosis and silences target genes PTEN and PDCD4 which in turn accounts for a net anti-inflammatory phenotype. Findings of this study highlight the significance of miRNAs in the resolution of wound inflammation. PMID:24391209

Estrogen Signaling in Metabolic Inflammation

PubMed Central

Monteiro, Rosário; Teixeira, Diana; Calhau, Conceição

2014-01-01

There is extensive evidence supporting the interference of inflammatory activation with metabolism. Obesity, mainly visceral obesity, is associated with a low-grade inflammatory state, triggered by metabolic surplus where specialized metabolic cells such as adipocytes activate cellular stress initiating and sustaining the inflammatory program. The increasing prevalence of obesity, resulting in increased cardiometabolic risk and precipitating illness such as cardiovascular disease, type 2 diabetes, fatty liver, cirrhosis, and certain types of cancer, constitutes a good example of this association. The metabolic actions of estrogens have been studied extensively and there is also accumulating evidence that estrogens influence immune processes. However, the connection between these two fields of estrogen actions has been underacknowledged since little attention has been drawn towards the possible action of estrogens on the modulation of metabolism through their anti-inflammatory properties. In the present paper, we summarize knowledge on the modification inflammatory processes by estrogens with impact on metabolism and highlight major research questions on the field. Understanding the regulation of metabolic inflammation by estrogens may provide the basis for the development of therapeutic strategies to the management of metabolic dysfunctions. PMID:25400333

Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition.

PubMed

Ibrahim, Sherrine A; Ackerman, William E; Summerfield, Taryn L; Lockwood, Charles J; Schatz, Frederick; Kniss, Douglas A

2016-02-01

Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood. The principal goal of the work was to examine the inflammatory genomic profile of human decidual cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of decidual stromal cells. The effects of interleukin-1β exposure on mature microRNA expression were tested in human decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time-polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions. Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate < 0.1), respectively, including induction of numerous cytokines, chemokines, and other inflammatory mediators. Whereas this transcriptional response included marked changes in several microRNA gene loci, the pool of fully processed, mature microRNA was comparatively stable following a cytokine challenge. Of a total of 6 mature microRNAs identified as being differentially expressed by NanoString profiling, 2 (miR-146a and miR-155) were validated by quantitative real time-polymerase chain reaction. Using complementary bioinformatics approaches, activation of several inflammatory transcription factors could be inferred downstream of interleukin-1β based on the overall transcriptional response. Further analysis revealed that miR-146a and miR-155 both target genes involved in inflammatory signaling, including Toll-like receptor and mitogen-activated protein kinase pathways. Stimulation of decidual cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance. Copyright © 2016 Elsevier Inc. All rights reserved.

The Gastrointestinal Microbiome and Musculoskeletal Diseases: A Beneficial Role for Probiotics and Prebiotics

PubMed Central

Vitetta, Luis; Coulson, Samantha; Linnane, Anthony W.; Butt, Henry

2013-01-01

Natural medicines are an attractive option for patients diagnosed with common and debilitating musculoskeletal diseases such as Osteoarthritis (OA) or Rheumatoid Arthritis (RA). The high rate of self-medication with natural products is due to (1) lack of an available cure and (2) serious adverse events associated with chronic use of pharmaceutical medications in particular non-steroidal anti-inflammatory drugs (NSAIDs) and high dose paracetamol. Pharmaceuticals to treat pain may disrupt gastrointestinal (GIT) barrier integrity inducing GIT inflammation and a state of and hyper-permeability. Probiotics and prebiotics may comprise plausible therapeutic options that can restore GIT barrier functionality and down regulate pro-inflammatory mediators by modulating the activity of, for example, Clostridia species known to induce pro-inflammatory mediators. The effect may comprise the rescue of gut barrier physiological function. A postulated requirement has been the abrogation of free radical formation by numerous natural antioxidant molecules in order to improve musculoskeletal health outcomes, this notion in our view, is in error. The production of reactive oxygen species (ROS) in different anatomical environments including the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which is now well recognized as an essential second messenger required for normal cellular homeostasis and physiological function. The GIT commensal profile that tolerates the host does so by regulating pro-inflammatory and anti-inflammatory GIT mucosal actions through the activity of ROS signaling thereby controlling the activity of pathogenic bacterial species. PMID:25437335

Autophagy and kidney inflammation

PubMed Central

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-01-01

ABSTRACT Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases. PMID:28441075

Autophagy and kidney inflammation.

PubMed

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-06-03

Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases.

Biomimetic carbon monoxide delivery based on hemoglobin vesicles ameliorates acute pancreatitis in mice via the regulation of macrophage and neutrophil activity.

PubMed

Taguchi, Kazuaki; Nagao, Saori; Maeda, Hitoshi; Yanagisawa, Hiroki; Sakai, Hiromi; Yamasaki, Keishi; Wakayama, Tomohiko; Watanabe, Hiroshi; Otagiri, Masaki; Maruyama, Toru

2018-11-01

Macrophages play a central role in various inflammatory disorders and are broadly divided into two subpopulations, M1 and M2 macrophage. In the healing process in acute inflammatory disorders, shifting the production of M1 macrophages to M2 macrophages is desirable, because M1 macrophages secrete pro-inflammatory cytokines, whilst the M2 variety secrete anti-inflammatory cytokines. Previous findings indicate that when macrophages are treated with carbon monoxide (CO), the secretion of anti-inflammatory cytokine is increased and the expression of pro-inflammatory cytokines is inhibited, indicating that CO may have a potential to modulate the production of macrophages toward the M2-like phenotype. In this study, we examined the issue of whether CO targeting macrophages using a nanotechnology-based CO donor, namely CO-bound hemoglobin vesicles (CO-HbV), modulates their polarization and show therapeutic effects against inflammatory disorders. The results showed that the CO-HbV treatment polarized a macrophage cell line toward an M2-like phenotype. Furthermore, in an in vivo study using acute pancreatitis model mice as a model of an inflammatory disease, a CO-HbV treatment also tended to polarize macrophages toward an M2-like phenotype and inhibited neutrophil infiltration in the pancreas, resulting in a significant inflammation. In addition to the suppression of acute pancreatitis, CO-HbV diminished a subsequent pancreatitis-associated acute lung injury. This could be due to the inhibition of the systemic inflammation, neutrophil infiltration in the lungs and the production of HMGB-1. These findings suggest that CO-HbV exerts superior anti-inflammatory effects against inflammatory disorders via the regulation of macrophage and neutrophil activity.

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

PubMed Central

Viegas, Carla S. B.; Costa, Rúben M.; Santos, Lúcia; Videira, Paula A.; Silva, Zélia; Araújo, Nuna; Macedo, Anjos L.; Matos, António P.; Vermeer, Cees; Simes, Dina C.

2017-01-01

Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and γ-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein γ-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNFα, IL-1β and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application. PMID:28542410

Cryotherapy Reduces Inflammatory Response Without Altering Muscle Regeneration Process and Extracellular Matrix Remodeling of Rat Muscle

PubMed Central

Vieira Ramos, Gracielle; Pinheiro, Clara Maria; Messa, Sabrina Peviani; Delfino, Gabriel Borges; Marqueti, Rita de Cássia; Salvini, Tania de Fátima; Durigan, Joao Luiz Quagliotti

2016-01-01

The application of cryotherapy is widely used in sports medicine today. Cooling could minimize secondary hypoxic injury through the reduction of cellular metabolism and injury area. Conflicting results have also suggested cryotherapy could delay and impair the regeneration process. There are no definitive findings about the effects of cryotherapy on the process of muscle regeneration. The aim of the present study was to evaluate the effects of a clinical-like cryotherapy on inflammation, regeneration and extracellular matrix (ECM) remodeling on the Tibialis anterior (TA) muscle of rats 3, 7 and 14 days post-injury. It was observed that the intermittent application of cryotherapy (three 30-minute sessions, every 2 h) in the first 48 h post-injury decreased inflammatory processes (mRNA levels of TNF-α, NF-κB, TGF-β and MMP-9 and macrophage percentage). Cryotherapy did not alter regeneration markers such as injury area, desmin and Myod expression. Despite regulating Collagen I and III and their growth factors, cryotherapy did not alter collagen deposition. In summary, clinical-like cryotherapy reduces the inflammatory process through the decrease of macrophage infiltration and the accumulation of the inflammatory key markers without influencing muscle injury area and ECM remodeling. PMID:26725948

Beta-glucan-depleted, glycopeptide-rich extracts from Brewer's and Baker's yeast (Saccharomyces cerevisiae) lower interferon-gamma production by stimulated human blood cells in vitro.

PubMed

Williams, Roderick; Dias, Daniel A; Jayasinghe, Nirupama; Roessner, Ute; Bennett, Louise E

2016-04-15

Regulation of the human immune system requires controlled pro- and anti-inflammatory responses for host defence against infection and disease states. Yeasts (Saccharomyces cerevisiae), as used in brewing and baking, are mostly known for ability to stimulate the human immune-system predominantly reflecting the pro-inflammatory cell wall β-glucans. However, in this study, using food-compatible processing methods, glycopeptide-enriched and β-glucan-depleted products were each prepared from Brewer's and Baker's yeasts, which suppressed production of interferon-γ (IFN-γ) in human whole blood cell assay, signifying that anti-inflammatory factors are also present in yeast. Anti-inflammatory bioactivities of products prepared from Brewer's and Baker's yeast were compared with the commercial yeast product, Epicor®. While unfractionated Epicor was inactive, the C18 resin-binding fractions of Brewer's and Baker's yeast products and Epicor dose-dependently lowered IFN-γ, demonstrating that Epicor also contained both pro-inflammatory (β-glucans) and anti-inflammatory components. Anti-inflammatory activity was attributed to C18 resin-binding species glyco-peptides in Epicor and experimental yeast products. This study demonstrated that pro- and anti-inflammatory factors could be resolved and enriched in yeasts by suitable processing, with potential to improve specific activities. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Desloratadine citrate disodium injection, a potent histamine H(1) receptor antagonist, inhibits chemokine production in ovalbumin-induced allergic rhinitis guinea pig model and histamine-induced human nasal epithelial cells via inhibiting the ERK1/2 and NF-kappa B signal cascades.

PubMed

Chen, Meiling; Xu, Shuhong; Zhou, Peipei; He, Guangwei; Jie, Qiong; Wu, Yulin

2015-11-15

Chemokines have chemotactic properties on leukocyte subsets whose modulation plays a pivotal role in allergic inflammatory processes. Our present study was designed to investigate the anti-allergic and anti-inflammatory properties of desloratadine citrate disodium injection (DLC) and elucidate the molecular mechanisms of its anti-inflammatory properties. The anti-allergic effects of DLC were evaluated based on allergic symptoms, serological marker production and histological changes of the nasal mucosa in guinea pigs model of allergic rhinitis. The anti-inflammatory properties and molecular mechanisms of DLC were explored by studying the regulation of a set of chemokines and extracellular signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) pathways, after DLC treatment in guinea pigs model of allergic rhinitis in vivo and histamine-activated human nasal epithelial cells (HNECs) in vitro. In vivo model in guinea pigs, DLC alleviated the rhinitis symptoms, inhibited inflammatory cells infiltration in nasal lavage fluid (NLF) and histamine, monocyte chemotactic protein (MCP)-1, regulated on activation normal T cell expressed, and presumably secreted (RANTEs) and interleukin (IL)-8 release in sera and P-ERK1/2 and NF-κB activation in nasal mucosa. In vitro, DLC markedly inhibited histamine-induced production of MCP-1, RANTEs and IL-8 and suppressed c-Raf, mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and ERK1/2 activation in HNECs. These results provide evidence that DLC possesses potent anti-allergic and anti-inflammatory properties. The mechanism of action underlying DLC in allergic inflammation appears to be inhibition of the phosphorylation of ERK1/2, in addition to blocking of the NF-κB pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro studies on the relationship between the anti-inflammatory activity of Physalis peruviana extracts and the phagocytic process.

PubMed

Martínez, Willington; Ospina, Luis Fernando; Granados, Diana; Delgado, Gabriela

2010-03-01

The study of plants used in traditional medicine has drawn the attention of researchers as an alternative in the development of new therapeutics agents, such as the American Solanaceae Physalis peruviana, which has significant anti-inflammatory activity. The Physalis peruviana anti-inflammatory effect of ethanol or ether calyces extracts on the phagocytic process was assessed by using an in vitro phagocytosis model (Leishmania panamensis infection to murine macrophages). The Physalis peruviana extracts do not inhibit microorganism internalization and have no parasiticide effect. Most ET and EP extracts negatively affected the parasite's invasion of macrophages (Infected cells increased.). This observation might result from a down-regulation of the macrophage's microbicide ability associated with a selective reduction of proinflammatory cytokines levels. Physalis peruviana's anti-inflammatory activity described in this model is related to an immunomodulatory effect exerted on macrophages infected, which directly or indirectly "blocks" their ability to secrete soluble proinflammatory mediators.

Understanding Resolvin Signaling Pathways to Improve Oral Health

PubMed Central

Keinan, David; Leigh, Noel J.; Nelson, Joel W.; De Oleo, Laura; Baker, Olga J.

2013-01-01

The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity. PMID:23528855

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States.

PubMed

Woller, Sarah A; Choi, Soo-Ho; An, Eun Jung; Low, Hann; Schneider, Dina A; Ramachandran, Roshni; Kim, Jungsu; Bae, Yun Soo; Sviridov, Dmitri; Corr, Maripat; Yaksh, Tony L; Miller, Yury I

2018-05-29

Apolipoprotein A-I binding protein (AIBP) reduces lipid raft abundance by augmenting the removal of excess cholesterol from the plasma membrane. Here, we report that AIBP prevents and reverses processes associated with neuroinflammatory-mediated spinal nociceptive processing. The mechanism involves AIBP binding to Toll-like receptor-4 (TLR4) and increased binding of AIBP to activated microglia, which mediates selective regulation of lipid rafts in inflammatory cells. AIBP-mediated lipid raft reductions downregulate LPS-induced TLR4 dimerization, inflammatory signaling, and expression of cytokines in microglia. In mice, intrathecal injections of AIBP reduce spinal myeloid cell lipid rafts, TLR4 dimerization, neuroinflammation, and glial activation. Intrathecal AIBP reverses established allodynia in mice in which pain states were induced by the chemotherapeutic cisplatin, intraplantar formalin, or intrathecal LPS, all of which are pro-nociceptive interventions known to be regulated by TLR4 signaling. These findings demonstrate a mechanism by which AIBP regulates neuroinflammation and suggest the therapeutic potential of AIBP in treating preexisting pain states. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

PubMed Central

Hanson, Daniel R; Gottesman, Irving I

2005-01-01

Background Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. Discussion A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. Summary A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons. PMID:15707482

The Dynamic Duo–Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases

PubMed Central

Li, Jun; Hsu, Hui-Chen; Mountz, John D.

2014-01-01

The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23+ inflammatory macrophages and IL-17+ GM-CSF+ CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context. PMID:25309946

Airborne nitro-PAHs induce Nrf2/ARE defense system against oxidative stress and promote inflammatory process by activating PI3K/Akt pathway in A549 cells.

PubMed

Shang, Yu; Zhou, Qian; Wang, Tiantian; Jiang, Yuting; Zhong, Yufang; Qian, Guangren; Zhu, Tong; Qiu, Xinghua; An, Jing

2017-10-01

Ambient particulate matter (PM) is a worldwide health issue of concern. However, limited information is available regarding the toxic contributions of the nitro-derivatives of polycyclic aromatic hydrocarbons (nitro-PAHs). This study intend to examine whether 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) could activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) antioxidant defense system, and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway participates in regulating pro-inflammatory responses in A549 cells. Firstly, 1-NP and 3-NF concentration-dependently induced cellular apoptosis, reactive oxygen species (ROS) generation, DNA damage, S phase cell cycle arrest and differential expression of related cytokine genes. Secondly, 1-NP and 3-NF activated the Nrf2/ARE defense system, as evidenced by increased protein expression levels and nuclear translocation of transcription factor Nrf2, elevated Nrf2/ARE binding activity, up-regulated expression of the target gene heme oxygenase-1 (HO-1). Significantly increased protein expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylation level of Akt indicated that the PI3K/Akt pathway was activated during pro-inflammatory process. Further, both PI3K inhibitor (LY294002) and Akt inhibitor (MK-2206) reversed the elevated TNF-α expression to control level. Our results suggested that Nrf2/ARE pathway activation might cause an initiation step in cellular protection against oxidative stress caused by nitro-PAHs, and the PI3K/Akt pathway participated in regulating inflammatory responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid

PubMed Central

Wang, Li-Chao; Wei, Wen-Hui; Zhang, Xiao-Wen; Liu, Dan; Zeng, Ke-Wu; Tu, Peng-Fei

2018-01-01

Drastic macrophages activation triggered by exogenous infection or endogenous stresses is thought to be implicated in the pathogenesis of various inflammatory diseases. Carnosic acid (CA), a natural phenolic diterpene extracted from Salvia officinalis plant, has been reported to possess anti-inflammatory activity. However, its role in macrophages activation as well as potential molecular mechanism is largely unexplored. In the current study, we sought to elucidate the anti-inflammatory property of CA using an integrated approach based on unbiased proteomics and bioinformatics analysis. CA significantly inhibited the robust increase of nitric oxide and TNF-α, downregulated COX2 protein expression, and lowered the transcriptional level of inflammatory genes including Nos2, Tnfα, Cox2, and Mcp1 in LPS-stimulated RAW264.7 cells, a murine model of peritoneal macrophage cell line. The LC-MS/MS-based shotgun proteomics analysis showed CA negatively regulated 217 LPS-elicited proteins which were involved in multiple inflammatory processes including MAPK, nuclear factor (NF)-κB, and FoxO signaling pathways. A further molecular biology analysis revealed that CA effectually inactivated IKKβ/IκB-α/NF-κB, ERK/JNK/p38 MAPKs, and FoxO1/3 signaling pathways. Collectively, our findings demonstrated the role of CA in regulating inflammation response and provide some insights into the proteomics-guided pharmacological mechanism study of natural products. PMID:29713284

HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

PubMed Central

Leus, Niek G. J.; van den Bosch, Thea; van der Wouden, Petra E.; Krist, Kim; Ourailidou, Maria E.; Eleftheriadis, Nikolaos; Kistemaker, Loes E. M.; Bos, Sophie; Gjaltema, Rutger A. F.; Mekonnen, Solomon A.; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J.; Dekker, Frank J.

2017-01-01

Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD. PMID:28344354

PUFA diets alter the microRNA expression profiles in an inflammation rat model.

PubMed

Zheng, Zheng; Ge, Yinlin; Zhang, Jinyu; Xue, Meilan; Li, Quan; Lin, Dongliang; Ma, Wenhui

2015-06-01

Omega‑3 and ‑6 polyunsaturated fatty acids (PUFAs) can directly or indirectly regulate immune homeostasis via inflammatory pathways, and components of these pathways are crucial targets of microRNAs (miRNAs). However, no study has examined the changes in the miRNA transcriptome during PUFA‑regulated inflammatory processes. Here, we established PUFA diet‑induced autoimmune‑prone (AP) and autoimmune‑averse (AA) rat models, and studied their physical characteristics and immune status. Additionally, miRNA expression patterns in the rat models were compared using microarray assays and bioinformatic methods. A total of 54 miRNAs were differentially expressed in common between the AP and the AA rats, and the changes in rno‑miR‑19b‑3p, ‑146b‑5p and ‑183‑5p expression were validated using stem‑loop reverse transcription‑quantitative polymerase chain reaction. To better understand the mechanisms underlying PUFA‑regulated miRNA changes during inflammation, computational algorithms and biological databases were used to identify the target genes of the three validated miRNAs. Furthermore, Gene Ontology (GO) term annotation and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in inflammatory pathways. The predicted PUFA‑regulated inflammatory pathways included the Toll‑like receptor (TLR), T cell receptor (TCR), NOD‑like receptor (NLR), RIG‑I‑like receptor (RLR), mitogen‑activated protein kinase (MAPK) and the transforming growth factor‑β (TGF‑β) pathway. This study is the first report, to the best of our knowledge, on in vivo comparative profiling of miRNA transcriptomes in PUFA diet‑induced inflammatory rat models using a microarray approach. The results provide a useful resource for future investigation of the role of PUFA‑regulated miRNAs in immune homeostasis.

Proteome and phosphoproteome analysis of commensally induced dendritic cell maturation states.

PubMed

Korkmaz, Ali Giray; Popov, Todor; Peisl, Loulou; Codrea, Marius Cosmin; Nahnsen, Sven; Steimle, Alexander; Velic, Ana; Macek, Boris; von Bergen, Martin; Bernhardt, Joerg; Frick, Julia-Stefanie

2018-05-30

Dendritic cells (DCs) can shape the immune system towards an inflammatory or tolerant state depending on the bacterial antigens and the environment they encounter. In this study we provide a proteomic catalogue of differentially expressed proteins between distinct DC maturation states, brought about by bacteria that differ in their endotoxicity. To achieve this, we have performed proteomics and phosphoproteomics on murine DC cultures. Symbiont and pathobiont bacteria were used to direct dendritic cells into a semi-mature and fully-mature state, respectively. The comparison of semi-mature and fully-mature DCs revealed differential expression in 103 proteins and differential phosphorylation in 118 phosphosites, including major regulatory factors of central immune processes. Our analyses predict that these differences are mediated by upstream elements such as SOCS1, IRF3, ABCA1, TLR4, and PTGER4. Our analyses indicate that the symbiont bacterial strain affects DC proteome in a distinct way, by downregulating inflammatory proteins and activating anti-inflammatory upstream regulators. Biological significance In this study we have investigated the responses of immune cells to distinct bacterial stimuli. We have used the symbiont bacterial strain B. vulgatus and the pathobiont E. coli strain to stimulate cultured primary dendritic cells and performed a shotgun proteome analysis to investigate the protein expression and phosphorylation level differences on a genome level. We have observed expression and phosphorylation level differences in key immune regulators, transcription factors and signal transducers. Moreover, our subsequent bioinformatics analysis indicated regulation at several signaling pathways such as PPAR signaling, LXR/RXR activation and glucocorticoid signaling pathways, which are not studied in detail in an inflammation and DC maturation context. Our phosphoproteome analysis showed differential phosphorylation in 118 phosphosites including those belonging to epigenetic regulators, transcription factors and major cell cycle regulators. We anticipate that our study will facilitate further investigation of immune cell proteomes under different inflammatory and non-inflammatory conditions. Copyright © 2017. Published by Elsevier B.V.

The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes

PubMed Central

2011-01-01

Background Reactive astrocytes are capable of producing a variety of pro-inflammatory mediators and potentially neurotoxic compounds, including nitric oxide (NO). High amounts of NO are synthesized following up-regulation of inducible NO synthase (iNOS). The expression of iNOS is tightly regulated by complex molecular mechanisms, involving both transcriptional and post-transcriptional processes. The mammalian target of rapamycin (mTOR) kinase modulates the activity of some proteins directly involved in post-transcriptional processes of mRNA degradation. mTOR is a serine-threonine kinase that plays an evolutionarily conserved role in the regulation of cell growth, proliferation, survival, and metabolism. It is also a key regulator of intracellular processes in glial cells. However, with respect to iNOS expression, both stimulatory and inhibitory actions involving the mTOR pathway have been described. In this study the effects of mTOR inhibition on iNOS regulation were evaluated in astrocytes. Methods Primary cultures of rat cortical astrocytes were activated with different proinflammatory stimuli, namely a mixture of cytokines (TNFα, IFNγ, and IL-1β) or by LPS plus IFNγ. Rapamycin was used at nM concentrations to block mTOR activity and under these conditions we measured its effects on the iNOS promoter, mRNA and protein levels. Functional experiments to evaluate iNOS activity were also included. Results In this experimental paradigm mTOR activation did not significantly affect astrocyte iNOS activity, but mTOR pathway was involved in the regulation of iNOS expression. Rapamycin did not display any significant effects under basal conditions, on either iNOS activity or its expression. However, the drug significantly increased iNOS mRNA levels after 4 h incubation in presence of pro-inflammatory stimuli. This stimulatory effect was transient, since no differences in either iNOS mRNA or protein levels were detected after 24 h. Interestingly, reduced levels of iNOS mRNA were detected after 48 hours, suggesting that rapamycin can modify iNOS mRNA stability. In this regard, we found that rapamycin significantly reduced the half-life of iNOS mRNA, from 4 h to 50 min when cells were co-incubated with cytokine mixture and 10 nM rapamycin. Similarly, rapamycin induced a significant up-regulation of tristetraprolin (TTP), a protein involved in the regulation of iNOS mRNA stability. Conclusion The present findings show that mTOR controls the rate of iNOS mRNA degradation in astrocytes. Together with the marked anti-inflammatory effects that we previously observed in microglial cells, these data suggest possible beneficial effects of mTOR inhibitors in the treatment of inflammatory-based CNS pathologies. PMID:21208419

Cognition and Emotions in Recurrent Depressive Disorders - The Role of Inflammation and the Kynurenine Pathway.

PubMed

Talarowska, Monika; Galecki, Piotr

2016-01-01

Separating emotions from cognition seems impossible in everyday experiences of a human being. Emotional processes have an impact on the ability of planning and solving problems, or decision-making skills. They are a valuable source of information about ourselves, our partners in interactions and the surrounding world. Recent years have shown that axial symptoms of depression are caused by emotion regulation disorders, dysfunctions in the reward system and deficits of cognitive processes. There is a few studies concerning a link between emotional and inflammatory processes in depression. The aim of this article is to present results of contemporary research studies over mutual connections between social cognition, cognitive processes and inflammatory factors significant for the aetiology of recurrent depressive disorders, with particular reference to the role of kynurenine pathways.

Borrelia burgdorferi infection induces lipid mediator production during Lyme arthritis.

PubMed

Brown, Charles R; Dennis, Edward A

2017-10-01

Experimental Lyme arthritis provides a mouse model for exploring the development of pathology following infection of C3H mice with Borrelia burgdorferi. Infected mice develop a reliable inflammatory arthritis of the ankle joint with severity that typically peaks around two to three weeks post-infection and then undergoes spontaneous resolution. This makes experimental Lyme arthritis an excellent model for investigating the mechanisms that drive both the development and resolution phases of inflammatory disease. Eicosanoids are powerful lipid mediators of inflammation and are known to regulate multiple aspects of inflammatory processes. While much is known about the role of eicosanoids in regulating immune responses during autoimmune disease and cancer, relatively little is known about their role during bacterial infection. In this review, we discuss the role of eicosanoid biosynthetic pathways in mediating inflammatory responses during bacterial infection using experimental Lyme arthritis as a model system. We point out the critical role eicosanoids play in disease development and highlight surprising differences between sterile autoimmune responses and those occurring in response to bacterial infection. These differences should be kept in mind when designing therapies and treatments for inflammatory diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Microbiota-specific Th17 cells: Yin and Yang in regulation of inflammatory bowel disease

PubMed Central

Wei, Wu; Feidi, Chen; Zhanju, Liu; Yingzi, Cong

2016-01-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria (LP) under steady conditions. Many studies have demonstrated that microbiota reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in patients with Crohn’s Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both pro-inflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis as well as in the pathogenesis of inflammatory bowel diseases. PMID:27057688

Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens

PubMed Central

2012-01-01

Glycogen synthase kinase 3β (GSK3β) plays a fundamental role during the inflammatory response induced by bacteria. Depending on the pathogen and its virulence factors, the type of cell and probably the context in which the interaction between host cells and bacteria takes place, GSK3β may promote or inhibit inflammation. The goal of this review is to discuss recent findings on the role of the inhibition or activation of GSK3β and its modulation of the inflammatory signaling in monocytes/macrophages and epithelial cells at the transcriptional level, mainly through the regulation of nuclear factor-kappaB (NF-κB) activity. Also included is a brief overview on the importance of GSK3 in non-inflammatory processes during bacterial infection. PMID:22691598

Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens.

PubMed

Cortés-Vieyra, Ricarda; Bravo-Patiño, Alejandro; Valdez-Alarcón, Juan J; Juárez, Marcos Cajero; Finlay, B Brett; Baizabal-Aguirre, Víctor M

2012-06-12

Glycogen synthase kinase 3β (GSK3β) plays a fundamental role during the inflammatory response induced by bacteria. Depending on the pathogen and its virulence factors, the type of cell and probably the context in which the interaction between host cells and bacteria takes place, GSK3β may promote or inhibit inflammation. The goal of this review is to discuss recent findings on the role of the inhibition or activation of GSK3β and its modulation of the inflammatory signaling in monocytes/macrophages and epithelial cells at the transcriptional level, mainly through the regulation of nuclear factor-kappaB (NF-κB) activity. Also included is a brief overview on the importance of GSK3 in non-inflammatory processes during bacterial infection.

Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease.

PubMed

Wu, Wei; Chen, Feidi; Liu, Zhanju; Cong, Yingzi

2016-06-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria under steady conditions. Many studies have demonstrated that microbiota-reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-interleukin-17A or anti-interleukin-17RA antibodies in patients with Crohn's Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both proinflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases.

Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution

PubMed Central

Fredman, Gabrielle; Serhan, Charles N.

2011-01-01

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators. PMID:21711247

Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but does not prevent inflammatory disease.

PubMed

Robb, Lorraine; Boyle, Kristy; Rakar, Steven; Hartley, Lynne; Lochland, Janelle; Roberts, Andrew W; Alexander, Warren S; Metcalf, Donald

2005-11-08

The suppressor of cytokine-signaling (SOCS) proteins act as negative-feedback inhibitors of cytokine and growth-factor-induced signal transduction. In vivo studies have implicated SOCS3 as a negative regulator of signaling downstream of gp130, the receptor subunit shared by IL-6-like cytokines. Mice lacking SOCS3 die at midgestation because of placental failure, and SOCS3 ablation in a cell-type-specific manner results in changes in the functional outcome of gp130 signaling in response to IL-6. In this study, we show that genetic reduction of leukemia-inhibitory factor (LIF) production by embryo-derived tissues is sufficient to prevent the placental defect. This establishes LIF signaling as a major physiological regulator of trophoblast differentiation in vivo. Mice deficient in both SOCS3 and LIF are born in predicted numbers and appear normal at birth but exhibit failure to thrive and high neonatal mortality. Adult SOCS3-null mice on a LIF-null background succumb to a spontaneous fatal inflammatory disease characterized by neutrophilia and inflammatory-cell tissue infiltrates. The disease spectrum mimics that seen in mice with a conditional deletion of SOCS3 in hematopoietic and endothelial cells, extending the evidence for a major role for SOCS3 in the homeostatic regulation of the inflammatory response and indicates that LIF is not required for this process.

Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but does not prevent inflammatory disease

PubMed Central

Robb, Lorraine; Boyle, Kristy; Rakar, Steven; Hartley, Lynne; Lochland, Janelle; Roberts, Andrew W.; Alexander, Warren S.; Metcalf, Donald

2005-01-01

The suppressor of cytokine-signaling (SOCS) proteins act as negative-feedback inhibitors of cytokine and growth-factor-induced signal transduction. In vivo studies have implicated SOCS3 as a negative regulator of signaling downstream of gp130, the receptor subunit shared by IL-6-like cytokines. Mice lacking SOCS3 die at midgestation because of placental failure, and SOCS3 ablation in a cell-type-specific manner results in changes in the functional outcome of gp130 signaling in response to IL-6. In this study, we show that genetic reduction of leukemia-inhibitory factor (LIF) production by embryo-derived tissues is sufficient to prevent the placental defect. This establishes LIF signaling as a major physiological regulator of trophoblast differentiation in vivo. Mice deficient in both SOCS3 and LIF are born in predicted numbers and appear normal at birth but exhibit failure to thrive and high neonatal mortality. Adult SOCS3-null mice on a LIF-null background succumb to a spontaneous fatal inflammatory disease characterized by neutrophilia and inflammatory-cell tissue infiltrates. The disease spectrum mimics that seen in mice with a conditional deletion of SOCS3 in hematopoietic and endothelial cells, extending the evidence for a major role for SOCS3 in the homeostatic regulation of the inflammatory response and indicates that LIF is not required for this process. PMID:16258063

Innate lymphoid cells in the initiation, regulation and resolution of inflammation

PubMed Central

Sonnenberg, Gregory F.; Artis, David

2016-01-01

A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans, and found to profoundly influence the induction, regulation and resolution of inflammation. ILCs play an important role in these processes in murine models of infection, inflammatory disease and tissue repair. Further, disease association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review, we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be employed to selectively modulate ILC responses and limit chronic inflammatory diseases in patients. PMID:26121198

Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

PubMed

Smith, Jeffrey S; Rajagopal, Sudarshan; Atwater, Amber Reck

2018-06-22

Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and β-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel ACD therapies and other inflammatory diseases.

Redox signaling in acute pancreatitis

PubMed Central

Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

2015-01-01

Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. PMID:25778551

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells*

PubMed Central

Kozela, Ewa; Pietr, Maciej; Juknat, Ana; Rimmerman, Neta; Levy, Rivka; Vogel, Zvi

2010-01-01

Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1β, interleukin-6, and interferon (IFN)β, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-κB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNβ-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-κB and IFNβ-dependent pathways. PMID:19910459

Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing.

PubMed

Hesketh, Mark; Sahin, Katherine B; West, Zoe E; Murray, Rachael Z

2017-07-17

Macrophages and inflammation play a beneficial role during wound repair with macrophages regulating a wide range of processes, such as removal of dead cells, debris and pathogens, through to extracellular matrix deposition re-vascularisation and wound re-epithelialisation. To perform this range of functions, these cells develop distinct phenotypes over the course of wound healing. They can present with a pro-inflammatory M1 phenotype, more often found in the early stages of repair, through to anti-inflammatory M2 phenotypes that are pro-repair in the latter stages of wound healing. There is a continuum of phenotypes between these ranges with some cells sharing phenotypes of both M1 and M2 macrophages. One of the less pleasant consequences of quick closure, namely the replacement with scar tissue, is also regulated by macrophages, through their promotion of fibroblast proliferation, myofibroblast differentiation and collagen deposition. Alterations in macrophage number and phenotype disrupt this process and can dictate the level of scar formation. It is also clear that dysregulated inflammation and altered macrophage phenotypes are responsible for hindering closure of chronic wounds. The review will discuss our current knowledge of macrophage phenotype on the repair process and how alterations in the phenotypes might alter wound closure and the final repair quality.

Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions

PubMed Central

Kolářová, Hana; Ambrůzová, Barbora; Švihálková Šindlerová, Lenka; Klinke, Anna; Kubala, Lukáš

2014-01-01

The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed. PMID:24803742

Cardiovascular and intestinal responses to oxidative and nitrosative stress during prolonged magnesium deficiency.

PubMed

Weglicki, William B; Chmielinska, Joanna J; Kramer, Jay H; Mak, I Tong

2011-08-01

In rodents with dietary magnesium deficiency (Mg deficiency), hypomagnesemia, occurs leading to a rise in circulating substance P from neuronal tissues to trigger systemic inflammatory stress in cardiac and intestinal tissues. Sustained elevations of substance P may result from impaired neutral endopeptidase (NEP) activity due to reactive oxygen and reactive nitrogen species. Associated increase in intestinal permeability includes infiltration of WBC and endotoxemia, which can further amplify the systemic inflammatory response that leads to impaired contractile function associated with up-regulation of the cardiac CD14 endotoxin receptor. The neurogenic signal transduction pathways that we have identified in the pro-oxidant/pro-inflammatory processes found with prolonged hypomagnesemia are described in this report.

Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis

PubMed Central

Collier, Christine; Griffin, Sholeem; Schuberth, Hans-Joachim; Sandra, Olivier; Smith, David G.; Mahan, Suman; Dieuzy-Labaye, Isabelle; Sheldon, I. Martin

2016-01-01

Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies. PMID:26673142

Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to Inflammation

PubMed Central

Benesova, Karolina; Vujić Spasić, Maja; Schaefer, Sebastian M.; Stolte, Jens; Baehr-Ivacevic, Tomi; Waldow, Katharina; Zhou, Zhe; Klingmueller, Ursula; Benes, Vladimir; Mall, Marcus A.; Muckenthaler, Martina U.

2012-01-01

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe−/− mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe−/− and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe−/− mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe−/− and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis. PMID:22745741

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis.

PubMed

Ramakrishna, Chandran; Cantin, Edouard M

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection.

MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor δ in human monocytes during the inflammatory response

PubMed Central

THULIN, PETRA; WEI, TIANLING; WERNGREN, OLIVERA; CHEUNG, LOUISA; FISHER, RACHEL M.; GRANDÉR, DAN; CORCORAN, MARTIN; EHRENBORG, EWA

2013-01-01

PPARδ is involved in the inflammatory response and its expression is induced by cytokines, however, limited knowledge has been produced regarding its regulation. Since recent findings have shown that microRNAs, which are small non-coding RNAs that regulate gene expression, are involved in the immune response, we set out to investigate whether PPARδ can be regulated by microRNAs expressed in monocytes. Bioinformatic analysis identified a putative miR-9 target site within the 3′-UTR of PPARδ that was subsequently verified to be functional using reporter constructs. Primary human monocytes stimulated with LPS showed a downregulation of PPARδ and its target genes after 4 h while the expression of miR-9 was induced. Analysis of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages showed that human PPARδ mRNA as well as miR-9 expression was higher in M1 compared to M2 macrophages. Furthermore, treatment with the PPARδ agonist, GW501516, induced the expression of PPARδ target genes in the pro-inflammatory M1 macrophages while no change was observed in the anti-inflammatory M2 macrophages. Taken together, these data suggest that PPARδ is regulated by miR-9 in monocytes and that activation of PPARδ may be of importance in M1 pro-inflammatory but not in M2 anti-inflammatory macrophages in humans. PMID:23525285

Mutual inhibition between HDAC9 and miR-17 regulates osteogenesis of human periodontal ligament stem cells in inflammatory conditions.

PubMed

Li, Liya; Liu, Wenjia; Wang, Hong; Yang, Qianjuan; Zhang, Liqiang; Jin, Fang; Jin, Yan

2018-04-24

Histone deacetylases (HDAC) plays important roles in the post-translational modifications of histone cores as well as non-histone targets. Many of them are involved in key inflammatory processes. Despite their importance, whether and how HDAC9 is regulated under inflammatory conditions remains unclear. The aim of this study was to evaluate the effects of HDAC9 under chronic inflammation condition in human periodontal ligament stromal cell (PDLSCs) and to explore the underlying regulatory mechanism. PDLSCs from healthy or periodontitis human tissue was compared. The therapeutic effects of HDAC inhibitors was determined in PDLSC pellet transplanted nude mice and LPS-induced rat periodontitis. We report that HDAC9 was the most affected HDAC family member under inflammatory conditions in PDLSCs. HDAC9 impaired osteogenic differentiation capacity of PDLSCs under inflammatory conditions. Downregulation of HDAC9 by HDAC inhibitors or si-HDAC9 rescued the osteogenic differentiation capacity of inflammatory PDLSC to a similar level with the healthy PDLSC. In this context, HDAC9 and miR-17 formed an inhibitory loop. The inhibition of miR-17 aggravated loss of calcified nodules in inflamed PDLSCs and interrupted the effect of HDAC inhibitor in rescuing osteogenesis. In vivo experiments using nude mice and LPS-induced periodontitis model confirmed that HDAC inhibitors could improve new bone formation. We conclude that HDAC inhibitors improved osteogenesis of PDLSCs in vitro and periodontitis in vivo.

Hyaluronan as an Immune Regulator in Human Diseases

PubMed Central

NOBLE, PAUL W.; LIANG, JIURONG; JIANG, DIANHUA

2010-01-01

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on a variety of cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage by interacting with TLR2 and TLR4 on these parenchymal cells. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and stem cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases. PMID:21248167

Contributions of Neutrophils to Resolution of Mucosal Inflammation

PubMed Central

Colgan, Sean P.; Ehrentraut, Stefan F.; Glover, Louise E.; Kominsky, Douglas J.; Campbell, Eric L.

2014-01-01

Neutrophil (PMN) recruitment from the blood stream into surrounding tissues involves a regulated series of events central to acute responses in host defense. Accumulation of PMN within mucosal tissues have historically been considered pathognomonic features of both acute and chronic inflammatory conditions. Historically PMNs have been deemed necessary but detrimental when recruited, given the potential for tissue damage that results from a variety of mechanisms. Recent work, however, has altered our preconcieved notions of PMN contributions to inflammatory processes. In particular, significant evidence implicates a central role for the PMN in triggering inflammatory resolution. Such mechanisms involve both metabolic and biochemical crosstalk pathways during the intimate interactions of PMN with other cell types at inflammatory sites. Here, we highlight several recent examples of how PMN coordinate the resolution of ongoing inflammation, with a particular focus on the gastrointestinal mucosa. PMID:22968707

5,7-Dihydroxyflavone Analogues May Regulate Lipopolysaccharide-Induced Inflammatory Responses by Suppressing IκBα-Linked Akt and ERK5 Phosphorylation in RAW 264.7 Macrophages

PubMed Central

Shimizu, Kazue; Koketsu, Mamoru; Ninomiya, Masayuki; Sato, Daisuke; Suzuki, Takashi; Hayakawa, Satoshi

2017-01-01

We studied the anti-inflammatory activity of twelve 5,7-dihydroxyflavone analogues in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. We found that chrysin (1) and 4′-methoxytricetin (9) showed relatively significant anti-inflammatory activity and low cytotoxicity. Moreover, 1 and 9 recovered the expression levels of iNOS and COX2, as well as those of the intracellular inflammatory mediators IL-1β and IL-6, which were upregulated by LPS stimulation. In addition, 1 and 9 actively regulated the phosphorylation of IκBα, leading to the activation of NFκB. Phosphorylation of Akt and ERK5 (upstream of NFκB) by LPS stimulation was significantly regulated by 1 and 9, as well as by BIX 02189 and LY 294002, which are phosphorylation inhibitors of ERK5 and Akt, respectively. The results suggest that compounds 1 and 9 may suppress the levels of iNOS and COX2 by regulating phosphorylation of Akt, ERK5, and IκBα and thus NFκB-related signaling pathways, resulting in anti-inflammatory effects in the cells. Because 1 and 9 showed low cytotoxicity and regulated both PGE2 and NO production caused by inflammatory responses, they may hold promise as natural anti-inflammatory agents. PMID:28539967

Design of peptide mimetics to block pro-inflammatory functions of HA fragments.

PubMed

Hauser-Kawaguchi, Alexandra; Luyt, Leonard G; Turley, Eva

2018-01-31

Hyaluronan is a simple extracellular matrix polysaccharide that actively regulates inflammation in tissue repair and disease processes. The native HA polymer, which is large (>500 kDa), contributes to the maintenance of homeostasis. In remodeling and diseased tissues, polymer size is strikingly polydisperse, ranging from <10 kDa to >500 kDa. In a diseased or stressed tissue context, both smaller HA fragments and high molecular weight HA polymers can acquire pro-inflammatory functions, which result in the activation of multiple receptors, triggering pro-inflammatory signaling to diverse stimuli. Peptide mimics that bind and scavenge HA fragments have been developed, which show efficacy in animal models of inflammation. These studies indicate both that HA fragments are key to driving inflammation and that scavenging these is a viable therapeutic approach to blunting inflammation in disease processes. This mini-review summarizes the peptide-based methods that have been reported to date for blocking HA signaling events as an anti-inflammatory therapeutic approach. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

The Transcriptomic Response of Rat Hepatic Stellate Cells to Endotoxin: Implications for Hepatic Inflammation and Immune Regulation

PubMed Central

Tandon, Ashish; Gandhi, Chandrashekhar R.

2013-01-01

With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS-stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFκB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFβ and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation. PMID:24349206

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products.

PubMed

Fuentes, Eduardo; Palomo, Iván

2013-01-01

Platelets are no longer considered simply as cells participating in thrombosis. In atherosclerosis, platelets are regulators of multiple processes, with the recruitment of inflammatory cells towards the lesion sites, inflammatory mediators release, and regulation of endothelial function. The antiplatelet therapy has been used for a long time in an effort to prevent and treat cardiovascular diseases. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy. In this context, a large number of natural products (polyphenols, terpenoids, alkaloids, and fatty acids) have been reported with antiplatelet activity. In this sense, the present paper describes mechanisms of antiplatelet action of natural products on platelet P-selectin expression through cAMP levels and its role as peroxisome proliferator-activated receptors agonists.

Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

PubMed Central

Busbee, Philip B; Rouse, Michael; Nagarkatti, Mitzi; Nagarkatti, Prakash S

2014-01-01

The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3+ regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID:23731446

Chemokine CCL28 induces apoptosis of decidual stromal cells via binding CCR3/CCR10 in human spontaneous abortion.

PubMed

Sun, Chan; Zhang, Yuan-Yuan; Tang, Chuan-Ling; Wang, Song-Cun; Piao, Hai-Lan; Tao, Yu; Zhu, Rui; Du, Mei-Rong; Li, Da-Jin

2013-10-01

Spontaneous abortion is the most common complication of pregnancy. Immune activation and the subsequent inflammation-induced tissue injury are often observed at the maternal-fetal interface as the final pathological assault in recurrent spontaneous abortion. However, the precise mechanisms responsible for spontaneous abortion involving inflammation are not fully understood. Chemokine CCL28 and its receptors CCR3 and CCR10 are important regulators in inflammatory process. Here, we examined the expression of CCL28 and its receptors in decidual stromal cells (DSCs) by immunochemistry and flow cytometry (FCM), and compared their expression level in DSCs from normal pregnancy versus spontaneous abortion, and their relationship to inflammatory cytokines production by DSCs. We further analyzed regulation of the pro-inflammatory cytokines on CCL28 expression in DSCs by real-time polymerase chain reaction, In-cell Western and FCM. The effects of CCL28-CCR3/CCR10 interaction on DSC apoptosis was investigated by Annexin V staining and FCM analysis or DAPI staining and nuclear morphology. Higher levels of the inflammatory cytokines interleukin (IL)-1β, IL-17A and tumor necrosis factor-α, and increased CCR3/CCR10 expression were observed in DSCs from spontaneous abortion compared with normal pregnancy. Treatment with inflammatory cytokines differently affected CCL28 and CCR3/CCR10 expression in DSCs. Human recombinant CCL28 promoted DSC apoptosis, which was eliminated by pretreatment with neutralizing antibodies against CCR3/CCR10 and CCL28. However, CCL28 did not affect DSC growth. These results suggest that the inflammation-promoted up-regulation of CCL28 and its receptors interaction in DSCs is involved in human spontaneous abortion via inducing DSC apoptosis.

LIGR, a protease-activated receptor-2-derived peptide, enhances skin pigmentation without inducing inflammatory processes.

PubMed

Lin, Connie B; Chen, Nannan; Scarpa, Richard; Guan, Fei; Babiarz-Magee, Laura; Liebel, Frank; Li, Wen-Hwa; Kizoulis, Menas; Shapiro, Stanley; Seiberg, Miri

2008-04-01

The protease-activated receptor-2 (PAR-2) is a seven transmembrane G-protein-coupled receptor that could be activated by serine protease cleavage or by synthetic peptide agonists. We showed earlier that activation of PAR-2 with Ser-Leu-Ile-Gly-Arg-Leu-NH(2) (SLIGRL), a known PAR-2 activating peptide, induces keratinocyte phagocytosis and increases skin pigmentation, indicating that PAR-2 regulates pigmentation by controlling phagocytosis of melanosomes. Here, we show that Leu-Ile-Gly-Arg-NH(2) (LIGR) can also induce skin pigmentation. Both SLIGRL and LIGR increased melanin deposition in vitro and in vivo, and visibly darkened human skins grafted onto severe combined immuno-deficient (SCID) mice. Both SLIGRL and LIGR stimulated Rho-GTP activation resulting in keratinocyte phagocytosis. Interestingly, LIGR activates only a subset of the PAR-2 signaling pathways, and unlike SLIGRL, it does not induce inflammatory processes. LIGR did not affect many PAR-2 signaling pathways, including [Ca(2+)] mobilization, cAMP induction, the induction of cyclooxgenase-2 (COX-2) expression and the secretion of prostaglandin E2, interleukin-6 and -8. PAR-2 siRNA inhibited LIGR-induced phagocytosis, indicating that LIGR signals via PAR-2. Our data suggest that LIGR is a more specific regulator of PAR-2-induced pigmentation relative to SLIGRL. Therefore, enhancing skin pigmentation by topical applications of LIGR may result in a desired tanned-like skin color, without enhancing inflammatory processes, and without the need of UV exposure.

Butyrate modulating effects on pro-inflammatory pathways in human intestinal epithelial cells.

PubMed

Elce, A; Amato, F; Zarrilli, F; Calignano, A; Troncone, R; Castaldo, G; Canani, R B

2017-10-13

Butyrate acts as energy source for intestinal epithelial cells and as key mediator of several immune processes, modulating gene expression mainly through histone deacetylation inhibition. Thanks to these effects, butyrate has been proposed for the treatment of many intestinal diseases. Aim of this study was to investigate the effect of butyrate on the expression of a large series of target genes encoding proteins involved in pro-inflammatory pathways. We performed quantitative real-time-PCR analysis of the expression of 86 genes encoding proteins bearing to pro-inflammatory pathways, before and after butyrate exposure, in primary epithelial cells derived from human small intestine and colon. Butyrate significantly down-regulated the expression of genes involved in inflammatory response, among which nuclear factor kappa beta, interferon-gamma, Toll like 2 receptor and tumour necrosis factor-alpha. Further confirmations of these data, including studies at protein level, would support the use of butyrate as effective therapeutic strategy in intestinal inflammatory disorders.

Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation.

PubMed

Pouliot, Marc; Fiset, Marie-Elaine; Massé, Mireille; Naccache, Paul H; Borgeat, Pierre

2002-11-01

Polymorphonuclear neutrophils (granulocytes; PMNs) are often the first blood cells to migrate toward inflammatory lesions to perform host defense functions. PMNs respond to specific stimuli by releasing several factors and generate lipid mediators of inflammation from the 5-lipoxygenase and the inducible cyclooxygenase (COX)-2 pathways. In view of adenosine's anti-inflammatory properties and suppressive impact on the 5-lipoxygenase pathway, we addressed in this study the impact of this autacoid on the COX-2 pathway. We observed that adenosine up-regulates the expression of the COX-2 enzyme and mRNA. Production of PGE(2) in response to exogenous arachidonic acid was also increased by adenosine and correlated with COX-2 protein levels. The potentiating effect of adenosine on COX-2 could be mimicked by pharmacological increases of intracellular cAMP levels, involving the latter as a putative second messenger for the up-regulation of COX-2 by adenosine. Specific COX-2 inhibitors were used to confirm the predominant role of the COX-2 isoform in the formation of prostanoids by stimulated PMNs. Withdrawal of extracellular adenosine strikingly emphasized the inhibitory potential of PGE(2) on leukotriene B(4) formation and involved the EP(2) receptor subtype in this process. Thus, adenosine may promote a self-limiting regulatory process through the increase of PGE(2) generation, which may result in the inhibition of PMN functions. This study identifies a new aspect of the anti-inflammatory properties of adenosine in leukocytes, introducing the concept that this autacoid may exert its immunomodulatory activities in part by modifying the balance of lipid mediators generated by PMNs.

Molecular Inflammation: Underpinnings of Aging and Age-related Diseases

PubMed Central

Chung, Hae Young; Cesari, Matteo; Anton, Stephen; Marzetti, Emanuele; Giovannini, Silvia; Seo, Arnold Young; Carter, Christy; Yu, Byung Pal; Leeuwenburgh, Christiaan

2013-01-01

Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL-1β, 6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-κB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity. PMID:18692159

Chronic Inflammatory Diseases and Green Tea Polyphenols

PubMed Central

Oz, Helieh S.

2017-01-01

Chronic inflammatory diseases affect millions of people globally and the incidence rate is on the rise. While inflammation contributes to the tissue healing process, chronic inflammation can lead to life-long debilitation and loss of tissue function and organ failure. Chronic inflammatory diseases include hepatic, gastrointestinal and neurodegenerative complications which can lead to malignancy. Despite the millennial advancements in diagnostic and therapeutic modalities, there remains no effective cure for patients who suffer from inflammatory diseases. Therefore, patients seek alternatives and complementary agents as adjunct therapies to relieve symptoms and possibly to prevent consequences of inflammation. It is well known that green tea polyphenols (GrTPs) are potent antioxidants with important roles in regulating vital signaling pathways. These comprise transcription nuclear factor-kappa B mediated I kappa B kinase complex pathways, programmed cell death pathways like caspases and B-cell lymphoma-2 and intervention with the surge of inflammatory markers like cytokines and production ofcyclooxygenase-2. This paper concisely reviews relevant investigations regarding protective effects of GrTPs and some reported adverse effects, as well as possible applications for GrTPs in the treatment of chronic and inflammatory complications. PMID:28587181

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis

PubMed Central

Ramakrishna, Chandran

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection. PMID:29352287

Pathophysiology of viral-induced exacerbations of COPD

PubMed Central

Alfredo, Potena; Gaetano, Caramori; Paolo, Casolari; Marco, Contoli; Johnston, Sebastian L; Alberto, Papi

2007-01-01

Inflammation of the lower airways is a central feature of chronic obstructive pulmonary disease (COPD). Inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. In most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. Transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. Many studies have suggested a role for viral infections as a causative agent of COPD exacerbations. In this review we will focus our attention on the relationship between common respiratory viral infections and the molecular and inflammatory mechanisms that lead to COPD exacerbation. PMID:18268922

Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Tsujimoto, Syunsuke; Tamura, Mizuho; So, Alexander; Yamanaka, Yoshihiro

2013-01-01

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes. PMID:24086554

Boric acid inhibits LPS-induced TNF-alpha formation through a thiol-dependent mechanism in THP-1 cells.

PubMed

Cao, Jun; Jiang, Liping; Zhang, Xiaomei; Yao, Xiaofeng; Geng, Chengyan; Xue, Xiangxin; Zhong, Laifu

2008-01-01

Oxidative stress plays an important role during inflammatory diseases and antioxidant administration to diminish oxidative stress may arrest inflammatory processes. Boron has been implicated to modulate certain inflammatory mediators and regulate inflammatory processes. Here we investigated the role of the tripeptide glutathione (GSH) in modulating the effects of boric acid (BA) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) formation in THP-1 monocytes. Interestingly, we found that BA had no significant effects on both TNF-alpha production and intracellular GSH contents, whereas it could inhibit LPS-induced TNF-alpha formation and ameliorated the d,l-buthionine-S,R-sulfoximine (BSO)-induced GSH depletion. Twenty-four hour incubation with BSO induced a decrease of the intracellular GSH and an increase of TNF-alpha. Treatment with N-acetyl-l-cysteine (NAC) did not significantly increase intracellular content of GSH but significantly reduced the secretion of TNF-alpha. BSO-pretreatment for 24h enhanced the LPS-induced secretion and mRNA expression of TNF-alpha further. BA inhibited LPS-stimulated TNF-alpha formation was also seen after GSH depletion by BSO. These results indicate that BA may have anti-inflammatory effect in the LPS-stimulated inflammation and the effect of BA on TNF-alpha secretion may be induced via a thiol-dependent mechanism.

Immune-regulating effects of exercise on cigarette smoke-induced inflammation

PubMed Central

Madani, Ashkan; Alack, Katharina; Richter, Manuel Jonas; Krüger, Karsten

2018-01-01

Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus–capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic antioxidative capacity and several compensatory mechanisms in tissues such as an increased anabolic signaling in muscle or an increased compliance of the vascular system. Accordingly, regular exercise training seems to protect long-term smokers against some important negative local and systemic consequences of smoking. Data suggest that it seems to be important to start exercise training as early as possible. PMID:29731655

A role for intracellular and extracellular DEK in regulating hematopoiesis.

PubMed

Capitano, Maegan L; Broxmeyer, Hal E

2017-07-01

Hematopoietic stem/progenitor cell fate decision during hematopoiesis is regulated by intracellular and extracellular signals such as transcription factors, growth factors, and cell-to-cell interactions. In this review, we explore the function of DEK, a nuclear phosphoprotein, on gene regulation. We also examine how DEK is secreted and internalized by cells, and discuss how both endogenous and extracellular DEK regulates hematopoiesis. Finally, we explore what currently is known about the regulation of DEK during inflammation. DEK negatively regulates the proliferation of early myeloid progenitor cells but has a positive effect on the differentiation of mature myeloid cells. Inflammation regulates intracellular DEK concentrations with inflammatory stimuli enhancing DEK expression. Inflammation-induced nuclear factor-kappa B activation is regulated by DEK, resulting in changes in the production of other inflammatory molecules such as IL-8. Inflammatory stimuli in turn regulates DEK secretion by cells of hematopoietic origin. However, how inflammation-induced expression and secretion of DEK regulates hematopoiesis remains unknown. Understanding how DEK regulates hematopoiesis under both homeostatic and inflammatory conditions may lead to a better understanding of the biology of HSCs and HPCs. Furthering our knowledge of the regulation of hematopoiesis will ultimately lead to new therapeutics that may increase the efficacy of hematopoietic stem cell transplantation.

ACF7 regulates inflammatory colitis and intestinal wound response by orchestrating tight junction dynamics

PubMed Central

Ma, Yanlei; Yue, Jiping; Zhang, Yao; Shi, Chenzhang; Odenwald, Matt; Liang, Wenguang G.; Wei, Qing; Goel, Ajay; Gou, Xuewen; Zhang, Jamie; Chen, Shao-Yu; Tang, Wei-Jen; Turner, Jerrold R.; Yang, Feng; Liang, Hong; Qin, Huanlong; Wu, Xiaoyang

2017-01-01

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD. PMID:28541346

TAM receptors regulate multiple features of microglial physiology.

PubMed

Fourgeaud, Lawrence; Través, Paqui G; Tufail, Yusuf; Leal-Bailey, Humberto; Lew, Erin D; Burrola, Patrick G; Callaway, Perri; Zagórska, Anna; Rothlin, Carla V; Nimmerjahn, Axel; Lemke, Greg

2016-04-14

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

mTOR Regulates Cellular Iron Homeostasis through Tristetraprolin

PubMed Central

Bayeva, Marina; Khechaduri, Arineh; Puig, Sergi; Chang, Hsiang-Chun; Patial, Sonika; Blackshear, Perry J.; Ardehali, Hossein

2013-01-01

SUMMARY Iron is an essential cofactor with unique redox properties. Iron regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron-requiring genes in both mammalian and yeast cells, and modulates survival in low-iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron regulatory pathways, and point towards the existence of a yeast-like TTP-mediated iron conservation program in mammals. PMID:23102618

Inflammation, Self-Regulation, and Health: An Immunologic Model of Self-Regulatory Failure.

PubMed

Shields, Grant S; Moons, Wesley G; Slavich, George M

2017-07-01

Self-regulation is a fundamental human process that refers to multiple complex methods by which individuals pursue goals in the face of distractions. Whereas superior self-regulation predicts better academic achievement, relationship quality, financial and career success, and lifespan health, poor self-regulation increases a person's risk for negative outcomes in each of these domains and can ultimately presage early mortality. Given its centrality to understanding the human condition, a large body of research has examined cognitive, emotional, and behavioral aspects of self-regulation. In contrast, relatively little attention has been paid to specific biologic processes that may underlie self-regulation. We address this latter issue in the present review by examining the growing body of research showing that components of the immune system involved in inflammation can alter neural, cognitive, and motivational processes that lead to impaired self-regulation and poor health. Based on these findings, we propose an integrated, multilevel model that describes how inflammation may cause widespread biobehavioral alterations that promote self-regulatory failure. This immunologic model of self-regulatory failure has implications for understanding how biological and behavioral factors interact to influence self-regulation. The model also suggests new ways of reducing disease risk and enhancing human potential by targeting inflammatory processes that affect self-regulation.

Adipokines and inflammation: is it a question of weight?

PubMed

Francisco, Vera; Pino, Jesus; Gonzalez-Gay, Miguel Angel; Mera, Antonio; Lago, Francisca; Gómez, Rodolfo; Mobasheri, Ali; Gualillo, Oreste

2018-05-01

Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders. © 2018 The British Pharmacological Society.

Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases.

PubMed

Solleiro-Villavicencio, Helena; Rivas-Arancibia, Selva

2018-01-01

In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4 + T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4 + T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration.

Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases

PubMed Central

Solleiro-Villavicencio, Helena; Rivas-Arancibia, Selva

2018-01-01

In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4+T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4+T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration. PMID:29755324

Evolutionary medicine and bone loss in chronic inflammatory diseases--A theory of inflammation-related osteopenia.

PubMed

Straub, Rainer H; Cutolo, Maurizio; Pacifici, Roberto

2015-10-01

Bone loss is typical in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, pemphigus vulgaris, and others. It is also typical in transplantation-related inflammation and during the process of aging. While we recognized that bone loss is tightly linked to immune system activation or inflamm-aging in the form of acute, chronic active, or chronic smoldering inflammation, bone loss is typically discussed to be an "accident of inflammation." Extensive literature search in PubMed central. Using elements of evolutionary medicine, energy regulation, and neuroendocrine regulation of homeostasis and immune function, we work out that bone waste is an adaptive, evolutionarily positively selected program that is absolutely necessary during acute inflammation. However, when acute inflammation enters a chronic state due to the inability to terminate inflammation (e.g., in autoimmunity or in continuous immunity against microbes), the acute program of bone loss is a misguided adaptive program. The article highlights the complexity of interwoven pathways of osteopenia. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways.

PubMed

Manteiga, Sara; Lee, Kyongbum

2017-04-01

A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals' effects on adult adipose tissue. Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor's activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ.

Evolutionary medicine and bone loss in chronic inflammatory diseases – a theory of inflammation-related osteopenia

PubMed Central

Straub, Rainer H.; Cutolo, Maurizio; Pacifici, Roberto

2015-01-01

Objective Bone loss is typical in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, pemphigus vulgaris, and others. It is also typical in transplantation-related inflammation and during the process of aging. While we recognized that bone loss is tightly linked to immune system activation or inflammaging in the form of acute, chronic active, or chronic smoldering inflammation, bone loss is typically discussed to be an “accident of inflammation”. Methods Extensive literature search in PubMed central. Results Using elements of evolutionary medicine, energy regulation, and neuroendocrine regulation of homeostasis and immune function, we work out that bone waste is an adaptive, evolutionarily positively selected program that is absolutely necessary during acute inflammation. However, when acute inflammation enters a chronic state due to the inability to terminate inflammation (e.g., in autoimmunity or in continuous immunity against microbes), the acute program of bone loss is a misguided adaptive program. Conclusions The article highlights the complexity of interwoven pathways of osteopenia. PMID:26044543

Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance - A review.

PubMed

Saini, Ramesh Kumar; Keum, Young-Soo

2018-06-15

Linoleic acid (LA) (n-6) and α-linolenic acid (ALA) (n-3) are essential fatty acids (EFAs) as they cannot be synthesized by humans or other higher animals. In the human body, these fatty acids (FAs) give rise to arachidonic acid (ARA, n-6), eicosapentaenoic acid (EPA, n-3), and docosahexaenoic acid (DHA, n-3) that play key roles in regulating body homeostasis. Locally acting bioactive signaling lipids called eicosanoids derived from these FAs also regulate diverse homeostatic processes. In general, ARA gives rise to pro-inflammatory eicosanoids whereas EPA and DHA give rise to anti-inflammatory eicosanoids. Thus, a proportionally higher consumption of n-3 PUFAs can protect us against inflammatory diseases, cancer, cardiovascular diseases, and other chronic diseases. The present review summarizes major sources, intake, and global consumption of n-3 and n-6 PUFAs. Their metabolism to biosynthesize long-chain PUFAs and eicosanoids and their roles in brain metabolism, cardiovascular disease, obesity, cancer, and bone health are also discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Pathophysiological Approaches of Acute Respiratory Distress syndrome: Novel Bases for Study of Lung Injury

PubMed Central

Castillo, R.L; Carrasco Loza, R; Romero-Dapueto, C

2015-01-01

Experimental approaches have been implemented to research the lung damage related-mechanism. These models show in animals pathophysiological events for acute respiratory distress syndrome (ARDS), such as neutrophil activation, reactive oxygen species burst, pulmonary vascular hypertension, exudative edema, and other events associated with organ dysfunction. Moreover, these approaches have not reproduced the clinical features of lung damage. Lung inflammation is a relevant event in the develop of ARDS as component of the host immune response to various stimuli, such as cytokines, antigens and endotoxins. In patients surviving at the local inflammatory states, transition from injury to resolution is an active mechanism regulated by the immuno-inflammatory signaling pathways. Indeed, inflammatory process is regulated by the dynamics of cell populations that migrate to the lung, such as neutrophils and on the other hand, the role of the modulation of transcription factors and reactive oxygen species (ROS) sources, such as nuclear factor kappaB and NADPH oxidase. These experimental animal models reproduce key components of the injury and resolution phases of human ALI/ARDS and provide a methodology to explore mechanisms and potential new therapies. PMID:26312099

Ox-LDL increases OX40L in endothelial cells through a LOX-1-dependent mechanism

PubMed Central

Dong, Q.; Xiang, R.; Zhang, D.Y.; Qin, S.

2013-01-01

Oxidative low-density lipoprotein (Ox-LDL) is a key risk factor for the development of atherosclerosis, and it can stimulate the expression of a variety of inflammatory signals. As a new and highly sensitive inflammation index, OX40L may be a key to understanding the mechanisms that regulate interactions between cells within the vessel wall and inflammatory mediators during the development of atherosclerosis. To investigate whether Ox-LDL regulates OX40L expression through an oxidized LDL-1 receptor (LOX-1)-mediated mechanism, we investigated the effect of different concentrations of Ox-LDL (50, 100, 150 µg/mL) on endothelial cell proliferation and apoptosis. Stimulation with Ox-LDL increased OX40L protein 1.44-fold and mRNA 4.0-fold in endothelial cells, and these effects were inhibited by blocking LOX-1. These results indicate that LOX-1 plays an important role in the chronic inflammatory process in blood vessel walls. Inhibiting LOX-1 may reduce blood vessel inflammation and provide a therapeutic option to limit atherosclerosis progression. PMID:24068192

Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections

PubMed Central

Faz-López, Berenice

2016-01-01

The Th1/Th2/Th17 balance is a fundamental feature in the regulation of the inflammatory microenvironment during helminth infections, and an imbalance in this paradigm greatly contributes to inflammatory disorders. In some cases of helminthiasis, an initial Th1 response could occur during the early phases of infection (acute), followed by a Th2 response that prevails in chronic infections. During the late phase of infection, alternatively activated macrophages (AAMs) are important to counteract the inflammation caused by the Th1/Th17 response and larval migration, limiting damage and repairing the tissue affected. Macrophages are the archetype of phagocytic cells, with the primary role of pathogen destruction and antigen presentation. Nevertheless, other subtypes of macrophages have been described with important roles in tissue repair and immune regulation. These types of macrophages challenge the classical view of macrophages activated by an inflammatory response. The role of these subtypes of macrophages during helminthiasis is a controversial topic in immunoparasitology. Here, we analyze some of the studies regarding the role of AAMs in tissue repair during the tissue migration of helminths. PMID:27648452

Niacin and its metabolites as master regulators of macrophage activation.

PubMed

Montserrat-de la Paz, Sergio; Naranjo, M Carmen; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J Garcia; Bermudez, Beatriz

2017-01-01

Niacin is a broad-spectrum lipid-regulating drug used for clinical therapy of chronic high-grade inflammatory diseases. However, the mechanisms by which either niacin or the byproducts of its catabolism ameliorate these inflammatory diseases are not clear yet. Human circulating monocytes and mature macrophages were used to analyze the effects of niacin and its metabolites (NAM, NUA and 2-Pyr) on oxidative stress, plasticity and inflammatory response by using biochemical, flow cytometry, quantitative real-time PCR and Western blot technologies. Niacin, NAM and 2-Pyr significantly decreased ROS, NO and NOS2 expression in LPS-treated human mature macrophages. Niacin and NAM skewed macrophage polarization toward antiinflammatory M2 macrophage whereas a trend toward proinflammatory M1 macrophage was noted following treatment with NUA. Niacin and NAM also reduced the inflammatory competence of LPS-treated human mature macrophages and promoted bias toward antiinflammatory CD14 + CD16 ++ nonclassical human primary monocytes. This study reveals for the first time that niacin and its metabolites possess antioxidant, reprogramming and antiinflammatory properties on human primary monocytes and monocyte-derived macrophages. Our findings imply a new understanding of the mechanisms by which niacin and its metabolites favor a continuous and gradual plasticity process in the human monocyte/macrophage system. Copyright © 2016 Elsevier Inc. All rights reserved.

[THE ROLE OF SYSTEM QUORUM SENSING UNDER CHRONIC UROGENITAL CHLAMYDIA INFECTION].

PubMed

2015-10-01

It is established that system quorum sensing (QS) assure social behavior of bacteria in regulation of genes of virulence and generalization of inflectional inflammatory process under chronic urogenital chlamydia infection. The techniques of gas chromatography and mass-spectrometry were applied to detect molecular markers of generalization of infectious process under urogenital chlamydiasis--activators of QS microbes (lactones, quinolones, furan ethers). The developed diagnostic gas chromatography and mass-spectrometry criteria of indexation of molecular markers under chronic urogenital chlamydia infection have high level of diagnostic sensitivity, specificity and prognostic value of positive and negative result. The application of techniques of gas chromatography and mass-spectrometry permits enhancing effectiveness of diagnostic of chronic inflectional inflammatory diseases of urogenital system of chlamydia etiology with identification of prognostic criteria of generalization of infectious process and subsequent prescription of timely and appropriate therapy

T Cell Intrinsic Function of the Noncanonical NF-κB Pathway in the Regulation of GM-CSF Expression and EAE Pathogenesis

PubMed Central

Yu, Jiayi; Zhou, Xiaofei; Nakaya, Mako; Jin, Wei; Cheng, Xuhong; Sun, Shao-Cong

2014-01-01

The Noncanonical NF-κB pathway induces processing of the NF-κB2 precursor protein p100 and, thereby, mediates activation of p52-containing NF-κB complexes. This pathway is crucial for B-cell maturation and humoral immunity, but its role in regulating T-cell function is less clear. Using mutant mice that express a non-processible p100, NF-κB2lym1, we show that the noncanonical NF-κB pathway has a T cell-intrinsic role in regulating the pathogenesis of a T cell-mediated autoimmunity, experimental autoimmune encephalomyelitis (EAE). Although the lym1 mutation does not interfere with naïve T-cell activation, it renders the Th17 cells defective in the production of inflammatory effector molecules, particularly the cytokine GM-CSF. We provide evidence that p52 binds to the promoter of the GM-CSF-encoding gene (Csf2) and cooperates with c-Rel in the transactivation of this target gene. Introduction of exogenous p52 or GM-CSF to the NF-κB2lym1 mutant T cells partially restores their ability to induce EAE. These results suggest that the noncanonical NF-κB pathway mediates induction of EAE by regulating the effector function of inflammatory T cells. PMID:24899500

A Novel Role for SIRT3 in Regulating Mediators Involved in the Terminal Pathways of Human Labor and Delivery.

PubMed

Lim, Ratana; Barker, Gillian; Menon, Ramkumar; Lappas, Martha

2016-11-01

Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators has been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2, and SIRT6 in regulating inflammation-induced prolabor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5, and SIRT7 expression in human myometrium. Functional studies were also used to investigate the effect of small interfering RNA (siRNA) knockdown of SIRTs in regulating inflammation-induced prolabor mediators. Western blot analysis and qRT-PCR were used to determine SIRT3, SIRT4, SIRT5, and SIRT7 mRNA and protein expression in human myometrium. Small interfering RNA knockdown of SIRT3 in myometrial primary cells determined its role in response to inflammatory stimuli IL1B and TNF. SIRT3 mRNA and protein expression levels were significantly lower in term laboring myometrium compared with term nonlaboring myometrium. There was no effect of labor on SIRT4, SIRT5 or SIRT7 protein expression. The pro-inflammatory cytokines IL1B and TNF significantly decreased levels of SIRT3 mRNA and protein expression. SIRT3 knockdown by siRNA significantly augmented IL1B- and TNF-stimulated IL6, CXCL8, and CCL2 mRNA expression and release; PTGS2 mRNA expression and subsequent PGF 2alpha release; the mRNA expression and secretion of the adhesion molecule ICAM1 and the extracellular matrix remodeling enzyme MMP9; and nuclear factor kappa B1 (NFkappaB1) transcriptional activity. In human myometrium, SIRT3 expression decreases with term labor and regulates the mediators involved in the terminal effector pathways of human labor and delivery through the NFkappaB1 pathway. © 2016 by the Society for the Study of Reproduction, Inc.

Anti-inflammatory Chitosan/Poly-γ-glutamic acid nanoparticles control inflammation while remodeling extracellular matrix in degenerated intervertebral disc.

PubMed

Teixeira, Graciosa Q; Leite Pereira, Catarina; Castro, Flávia; Ferreira, Joana R; Gomez-Lazaro, Maria; Aguiar, Paulo; Barbosa, Mário A; Neidlinger-Wilke, Cornelia; Goncalves, Raquel M

2016-09-15

Intervertebral disc (IVD) degeneration is one of the most common causes of low back pain (LBP), the leading disorder in terms of years lived with disability. Inflammation can play a role in LPB, while impairs IVD regeneration. In spite of this, different inflammatory targets have been purposed in the context of IVD regeneration. Anti-inflammatory nanoparticles (NPs) of Chitosan and Poly-(γ-glutamic acid) with a non-steroidal anti-inflammatory drug, diclofenac (Df), were previously shown to counteract a pro-inflammatory response of human macrophages. Here, the effect of intradiscal injection of Df-NPs in degenerated IVD was evaluated. For that, Df-NPs were injected in a bovine IVD organ culture in pro-inflammatory/degenerative conditions, upon stimulation with needle-puncture and interleukin (IL)-1β. Df-NPs were internalized by IVD cells, down-regulating IL-6, IL-8, MMP1 and MMP3, and decreasing PGE2 production, compared with IL-1β-stimulated IVD punches. Interestingly, at the same time, Df-NPs promoted an up-regulation of extracellular matrix (ECM) proteins, namely collagen type II and aggrecan. Allover, this study suggests that IVD treatment with Df-NPs not only reduces inflammation, but also delays and/or decreases ECM degradation, opening perspectives to new intradiscal therapies for IVD degeneration, based on the modulation of inflammation. Degeneration of the IVD is an age-related progressive process considered to be the major cause of spine disorders. The pro-inflammatory environment and biomechanics of the degenerated IVD is a challenge for regenerative therapies. The novelty of this work is the intradiscal injection of an anti-inflammatory therapy based on Chitosan (Ch)/Poly-(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) with an anti-inflammatory drug (diclofenac, Df), previously developed by us. This drug delivery system was tested in a pro-inflammatory/degenerative intervertebral disc ex vivo model. The main findings support the success of an anti-inflammatory therapy for degenerated IVD that not only reduces inflammation but also promotes native IVD matrix production. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lactobacillus acidophilus alleviates the inflammatory response to enterotoxigenic Escherichia coli K88 via inhibition of the NF-κB and p38 mitogen-activated protein kinase signaling pathways in piglets.

PubMed

Li, Haihua; Zhang, Lei; Chen, Longbin; Zhu, Qi; Wang, Wenjie; Qiao, Jiayun

2016-11-10

A newly isolated L. acidophilus strain has been reported to have potential anti-inflammatory activities against lipopolysaccharide (LPS) challenge in piglet, while the details of the related inflammatory responses are limited. Here we aimed to analysis the ability of L. acidophilus to regulate inflammatory responses and to elucidate the mechanisms involved in its anti-inflammatory activity. The ETEC (enterotoxigenic Escherichia coli) K88-induced up-regulations of IL-1β, IL-8 and TNF-α were obviously inhibited by L. acidophilus while IL-10 was significantly increased. Moreover, L. acidophilus down-regulated pattern recognition receptors TLR (Toll-like receptor) 2 and TLR4 expression in both spleen and mesenteric lymph nodes of ETEC-challenged piglets, in accompanied with the reduced phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and mitogen-activated protein kinase (MAPK) p38 as well in spleen of ETEC-infected piglets. Furthermore, L.acidophilus significantly increased the expression of the negative regulators of TLRs signaling, including Tollip, IRAK-M, A20 and Bcl-3 in spleen of ETEC-challenged piglets. Our findings suggested that L. acidophilus regulated inflammatory response to ETEC via impairing both NF-κB and MAPK signaling pathways in piglets.

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products

PubMed Central

Fuentes, Eduardo; Palomo, Iván

2013-01-01

Platelets are no longer considered simply as cells participating in thrombosis. In atherosclerosis, platelets are regulators of multiple processes, with the recruitment of inflammatory cells towards the lesion sites, inflammatory mediators release, and regulation of endothelial function. The antiplatelet therapy has been used for a long time in an effort to prevent and treat cardiovascular diseases. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy. In this context, a large number of natural products (polyphenols, terpenoids, alkaloids, and fatty acids) have been reported with antiplatelet activity. In this sense, the present paper describes mechanisms of antiplatelet action of natural products on platelet P-selectin expression through cAMP levels and its role as peroxisome proliferator-activated receptors agonists. PMID:24324520

Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala

PubMed Central

Anderson, George; Maes, Michael

2014-01-01

The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigenetic and environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant interactive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects centrally via the regulation of astrocyte and microglia responses, including regional variations in TRYCATs produced. Here we review the nature of these interactions and propose an early developmental model whereby different ASD genetic susceptibilities interact with environmental and epigenetic processes, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin and N-acetylserotonin production by immune and glia cells may be a significant treatment target. PMID:24669209

Multiple Inflammatory Cytokines Converge to Regulate CD8+ T cell Expansion and Function During Tuberculosis

PubMed Central

Booty, Matthew G.; Nunes-Alves, Cláudio; Carpenter, Stephen M.; Jayaraman, Pushpa; Behar, Samuel M.

2015-01-01

The differentiation of effector CD8+ T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. Here, we define three signals regulating CD8+ T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12, type I IFN, and IL-27. Using mixed bone marrow chimeras, we compared wild type and cytokine receptor knockout CD8+ T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks post-infection, IL-12, type 1 IFN, and IL-27 were all required for efficient CD8+ T cell expansion in the lungs. We next determined if these cytokines directly promote CD8+ T cell priming or are required only for expansion in the lungs. Utilizing retrogenic CD8+ T cells specific for the Mtb antigen TB10.4 (EsxH), we observed that IL-12 is the dominant cytokine driving both CD8+ T cell priming in the lymph node and expansion in the lungs; however, type I IFN and IL-27 have non-redundant roles supporting pulmonary CD8+ T cell expansion. Thus, IL-12 is a major signal promoting priming in the lymph node, but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore, these cytokines regulate the differentiation and function of CD8+ T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8+ T cell regulation during tuberculosis. PMID:26755819

The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling.

PubMed

Devallière, Julie; Charreau, Béatrice

2011-11-15

A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target. Copyright © 2011 Elsevier Inc. All rights reserved.

S100-alarmins: potential therapeutic targets for arthritis.

PubMed

Austermann, Judith; Zenker, Stefanie; Roth, Johannes

2017-07-01

In arthritis, inflammatory processes are triggered by numerous factors that are released from joint tissues, promoting joint destruction and pathological progression. During inflammation, a novel family of pro-inflammatory molecules called alarmins is released, amplifying inflammation and joint damage. Areas covered: With regard to the role of the alarmins S100A8 and S100A9 in the pathogenesis of arthritis, recent advances and the future prospects in terms of therapeutic implications are considered. Expert opinion: There is still an urgent need for novel treatment strategies addressing the local mechanisms of joint inflammation and tissue destruction, offering promising therapeutic alternatives. S100A8 and S100A9, which are the most up-regulated alarmins during arthritis, are endogenous triggers of inflammation, defining these proteins as promising targets for local suppression of arthritis. In murine models, the blockade of S100A8/S100A9 ameliorates inflammatory processes, including arthritis, and there are several lines of evidence that S100-alarmins may already be targeted in therapeutic approaches in man.

The dual personalities of matrix metalloproteinases in inflammation.

PubMed

Le, Nghia T V; Xue, Meilang; Castelnoble, Laura A; Jackson, Christopher J

2007-01-01

Collagen, gelatin, elastin, fibronectin, proteoglycans and vitronectin are just a few proteins which form the "mesh" that holds a multicellular organism together. The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade the extracellular matrix. Over several decades it has been clearly established that MMPs are the key molecules associated with matrix remodeling. The remodeling of this matrix is important for physiological and pathological processes such as pregnancy, wound repair, cancer and arthritis. The identification of new non-matrix MMP substrates involved in inflammation, highlights the diverse role of MMPs. These enzymes can enhance leukocyte invasion and regulate the inflammatory activity of serine proteases, cytokines and chemokines. Interestingly, the MMP family appears to have a "dual personality" in that several MMPs such as MMP-2 and -9 can favour either anti- or pro-inflammatory action, respectively. The extent of this dual functionality of MMPs is yet to be realized. Elucidating these processes may assist in the development of drugs for the treatment of inflammatory diseases such as arthritis, cancer and chronic wounds.

Source of Chronic Inflammation in Aging.

PubMed

Sanada, Fumihiro; Taniyama, Yoshiaki; Muratsu, Jun; Otsu, Rei; Shimizu, Hideo; Rakugi, Hiromi; Morishita, Ryuichi

2018-01-01

Aging is a complex process that results from a combination of environmental, genetic, and epigenetic factors. A chronic pro-inflammatory status is a pervasive feature of aging. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as "inflammaging" and represents a significant risk factor for morbidity and mortality in the elderly. The low-grade inflammation persists even after reversing pro-inflammatory stimuli such as LDL cholesterol and the renin-angiotensin system (RAS). Recently, several possible sources of chronic low-grade inflammation observed during aging and age-related diseases have been proposed. Cell senescence and dysregulation of innate immunity is one such mechanism by which persistent prolonged inflammation occurs even after the initial stimulus has been removed. Additionally, the coagulation factor that activates inflammatory signaling beyond its role in the coagulation system has been identified. This signal could be a new source of chronic inflammation and cell senescence. Here, we summarized the factors and cellular pathways/processes that are known to regulate low-grade persistent inflammation in aging and age-related disease.

Role of Osmolytes in Regulating Immune System.

PubMed

Kumar, Tarun; Yadav, Manisha; Singh, Laishram Rajendrakumar

2016-01-01

The immune system has evolved to protect the host organism from diverse range of pathogenic microbes that are themselves constantly evolving. It is a complex network of cells, humoral factors, chemokines and cytokines. Dysregulation of immune system results in various kinds of immunological disorders. There are several external agents which govern the regulation of immune system. Recent studies have indicated the role of osmolytes in regulation of various immunological processes such as Ag-Ab interaction, Ig assembly, Ag presentation etc. In this present review, we have systematically discussed the role of osmolytes involved in regulation of several key immunological processes. Osmolytes are involved in the regulation of several key immunological processes such as immunoglobulin assembly and folding, immune cells proliferation, regulation of immune cells function, Ag-Ab interaction, antigen presentation, inflammatory response and protection against photo-immunosuppression. Hence, osmolytes and their transporters might be used as potential drug and drug targets respectively. This review is therefore designed to help clinicians in development of osmolyte based therapeutic strategies in the treatment of various immunological disorders. Appropriate future perspectives have also been included.

Early environments and the ecology of inflammation

PubMed Central

McDade, Thomas W.

2012-01-01

Recent research has implicated inflammatory processes in the pathophysiology of a wide range of chronic degenerative diseases, although inflammation has long been recognized as a critical line of defense against infectious disease. However, current scientific understandings of the links between chronic low-grade inflammation and diseases of aging are based primarily on research in high-income nations with low levels of infectious disease and high levels of overweight/obesity. From a comparative and historical point of view, this epidemiological situation is relatively unique, and it may not capture the full range of ecological variation necessary to understand the processes that shape the development of inflammatory phenotypes. The human immune system is characterized by substantial developmental plasticity, and a comparative, developmental, ecological framework is proposed to cast light on the complex associations among early environments, regulation of inflammation, and disease. Recent studies in the Philippines and lowland Ecuador reveal low levels of chronic inflammation, despite higher burdens of infectious disease, and point to nutritional and microbial exposures in infancy as important determinants of inflammation in adulthood. By shaping the regulation of inflammation, early environments moderate responses to inflammatory stimuli later in life, with implications for the association between inflammation and chronic diseases. Attention to the eco-logics of inflammation may point to promising directions for future research, enriching our understanding of this important physiological system and informing approaches to the prevention and treatment of disease. PMID:23045646

Signaling by Antibodies: Recent Progress

PubMed Central

Bournazos, Stylianos; Wang, Taia T.; Dahan, Rony; Maamary, Jad; Ravetch, Jeffrey V.

2017-01-01

IgG antibodies mediate a diversity of immune functions by coupling of antigen specificity through the Fab domain to signal transduction via Fc-Fc receptor interactions. Indeed, balanced IgG signaling through Type I and Type II Fc receptors is required for the control of pro-inflammatory, anti-inflammatory, and immunomodulatory processes. In this review, we discuss the mechanisms that govern IgG-Fc receptor interactions, highlighting the diversity of Fc receptor-mediated effector functions that regulate immunity and inflammation, as well as determine susceptibility to infection and autoimmunity, and responsiveness to antibody-based therapeutics, and vaccine responses. PMID:28446061

Inhibition of Na+/H+ exchanger 1 by cariporide reduces burn-induced intestinal barrier breakdown.

PubMed

Yang, Xuekang; Chen, Ji; Bai, Hua; Tao, Ke; Zhou, Qin; Hou, Hongyi; Hu, Dahai

2013-12-01

Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

PubMed Central

Scortegagna, Marzia; Cataisson, Christophe; Martin, Rebecca J.; Hicklin, Daniel J.; Schreiber, Robert D.; Yuspa, Stuart H.

2008-01-01

Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression. PMID:18199827

C-Terminal Clipping of Chemokine CCL1/I-309 Enhances CCR8-Mediated Intracellular Calcium Release and Anti-Apoptotic Activity

PubMed Central

Denis, Catherine; Deiteren, Kathleen; Mortier, Anneleen; Tounsi, Amel; Fransen, Erik; Proost, Paul; Renauld, Jean-Christophe; Lambeir, Anne-Marie

2012-01-01

Carboxypeptidase M (CPM) targets the basic amino acids arginine and lysine present at the C-terminus of peptides or proteins. CPM is thought to be involved in inflammatory processes. This is corroborated by CPM-mediated trimming and modulation of inflammatory factors, and expression of the protease in inflammatory environments. Since the function of CPM in and beyond inflammation remains mainly undefined, the identification of natural substrates can aid in discovering the (patho)physiological role of CPM. CCL1/I-309, with its three C-terminal basic amino acids, forms a potential natural substrate for CPM. CCL1 plays a role not only in inflammation but also in apoptosis, angiogenesis and tumor biology. Enzymatic processing differently impacts the biological activity of chemokines thereby contributing to the complex regulation of the chemokine system. The aim of the present study was to investigate whether (i) CCL1/I-309 is prone to trimming by CPM, and (ii) the biological activity of CCL1 is altered after C-terminal proteolytic processing. CCL1 was identified as a novel substrate for CPM in vitro using mass spectrometry. C-terminal clipping of CCL1 augmented intracellular calcium release mediated by CCR8 but reduced the binding of CCL1 to CCR8. In line with the higher intracellular calcium release, a pronounced increase of the anti-apoptotic activity of CCL1 was observed in the BW5147 cellular model. CCR8 signaling, CCR8 binding and anti-apoptotic activity were unaffected when CPM was exposed to the carboxypeptidase inhibitor DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid. The results of this study suggest that CPM is a likely candidate for the regulation of biological processes relying on the CCL1-CCR8 system. PMID:22479563

Endoplasmic Reticulum Stress Mediates the Anti-Inflammatory Effect of Ethyl Pyruvate in Endothelial Cells

PubMed Central

Yi, Wei; Yang, Yang; Zhao, Dajun; Yang, Honggang; Geng, Ting; Xing, Jianzhou; Zhang, Yu; Tan, Songtao; Yi, Dinghua

2014-01-01

Ethyl pyruvate (EP) is a simple aliphatic ester of the metabolic intermediate pyruvate that has been demonstrated to be a potent anti-inflammatory agent in a variety of in vivo and in vitro model systems. However, the protective effects and mechanisms underlying the actions of EP against endothelial cell (EC) inflammatory injury are not fully understood. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of EC inflammation. In this study, our aim was to explore the effects of EP on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human umbilical vein endothelial cells (HUVECs) and to explore the role of ERS in this process. TNF-α treatment not only significantly increased the adhesion of monocytes to HUVECs and inflammatory cytokine (sICAM1, sE-selectin, MCP-1 and IL-8) production in cell culture supernatants but it also increased ICAM and MMP9 protein expression in HUVECs. TNF-α also effectively increased the ERS-related molecules in HUVECs (GRP78, ATF4, caspase12 and p-PERK). EP treatment effectively reversed the effects of the TNF-α-induced adhesion of monocytes on HUVECs, inflammatory cytokines and ERS-related molecules. Furthermore, thapsigargin (THA, an ERS inducer) attenuated the protective effects of EP against TNF-α-induced inflammatory injury and ERS. The PERK siRNA treatment not only inhibited ERS-related molecules but also mimicked the protective effects of EP to decrease TNF-α-induced inflammatory injury. In summary, we have demonstrated for the first time that EP can effectively reduce vascular endothelial inflammation and that this effect at least in part depends on the attenuation of ERS. PMID:25470819

Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology.

PubMed

Harizi, Hedi; Corcuff, Jean-Benoît; Gualde, Norbert

2008-10-01

Arachidonic acid (AA)-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes. They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodelling, cancer, asthma, rheumatoid arthritis and autoimmune disorders. Here, we review the major properties of eicosanoids and their expanding roles in biology and medicine.

Toll-like receptor signaling and its relevance to intestinal inflammation.

PubMed

Cario, Elke; Podolsky, Daniel K

2006-08-01

This review discusses the current progress in the understanding of how commensal-mediated activation of toll-like receptors (TLRs) may be involved in the regulation of physiological and pathophysiological processes of the intestinal mucosa including tissue regeneration and inflammation. While regulation of TLRs and their downstream signaling mediators might be used to prevent and treat inflammatory bowel diseases, paradoxically, at this time, it remains uncertain whether this would be more effectively accomplished by enhancing or inhibiting these pathways.

Inflammatory pathways in children with insufficient or disordered sleep.

PubMed

Kim, Jinkwan; Hakim, Fahed; Kheirandish-Gozal, Leila; Gozal, David

2011-09-30

Sleep is not only an essential physiological function, but also serves important roles in promoting growth, maturation, and overall health of children and adolescents. There is increasing interest regarding the impact of sleep and its disorders on the regulation of inflammatory processes and end-organ morbidities, particularly in the context of metabolic and cardiovascular diseases (CVD) and their complications. Obstructive sleep apnea syndrome (OSAS) is an increasingly common health problem in children, and in the last decade, the emergence of increasing obesity rates has further led to remarkable increases in the prevalence of OSAS, along with more prominent neurocognitive, behavioral, cardiovascular and metabolic morbidities. Although the underlying mechanisms leading to OSAS-induced morbidities are likely multi-factorial, and remain to be fully elucidated, activation of inflammatory pathways by OSAS has emerged as an important pathophysiological component of the end-organ injury associated with this disorder. To this effect, it would appear that OSAS could be viewed as a chronic, low-grade inflammatory disorder. Furthermore, the concurrent presence of obesity and OSAS poses a theoretically increased risk of OSAS-related complications. In this review, we will critically review the current state of research regarding the impact of insufficient and disrupted sleep and OSAS on the immune processes and inflammatory pathways that underlie childhood OSAS as a distinctive systemic inflammatory condition in children, and will explore potential interactions between OSAS and obesity. Copyright © 2011 Elsevier B.V. All rights reserved.

Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity.

PubMed

Jasson, Fiona; Nagy, Istvan; Knol, Anne Chantal; Zuliani, Thomas; Khammari, Amir; Dréno, Brigitte

2013-09-01

Acne is a chronic inflammatory illness of the pilosebaceous follicle where innate immunity plays a central role. In acne, the density of Propionibacterium acnes is increased in the pilosebaceous unit. We hypothesized that the severity of acne is not only dependent on the proliferation of P. acnes but also dependent on the pro-inflammatory potential of P. acnes strains and consequently constitutes potential triggering factor for acne scarring. We investigated pro-inflammatory potential of five different strains of P. acnes and P. avidum in skin explants and the preventive effect of zinc gluconate. The expression of immune markers was studied by immunohistochemistry, RT-qPCR and ELISA. P. acnes strains modulate differently the expression of immune markers both at gene and at protein levels. P. acnes type III had the highest pro-inflammatory potential by up-regulating the expression of PAR-2, TNF-alpha, MMP-13 and TIMP-2, whereas P. avidum had the weakest by up-regulating only MMP-13 and TIMP-2. Preincubation of zinc gluconate, which is a modulator of innate immunity, down-regulates the expression of most immune markers induced by P. acnes, PAR-2, TIMP-2, up-regulates MMP-1, TIMP-1. Our results demonstrate that different P. acnes strains have different inflammatory potential targeting markers of cutaneous innate immunity, and that inflammatory potential can be down-regulated by zinc gluconate. As such, the inflammatory potential of P. acnes strains on acne skin may influence the severity of inflammatory acne lesions and scars. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes.

PubMed

Rajasekhar, Pradeep; Poole, Daniel P; Veldhuis, Nicholas A

2017-01-01

Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein. © 2017 Elsevier Inc. All rights reserved.

Neuroinflammation and ageing: current theories and an overview of the data.

PubMed

Pizza, Vincenzo; Agresta, Anella; D'Acunto, Cosimo W; Festa, Michela; Capasso, Anna

2011-09-01

The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. This review will address the current understanding of the relationship between ageing and several factors both genetics and life style related. Firstly we focused on the most reliable and commonly shared theories which attempt to explain the phenomenon of ageing as the genetic, cellular, neuroendocrine, immunological and free-radicals related theories. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called "inflammaging", partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. In this review special attention was dedicated to diseases related to age as atherosclerosis, cancer and Alzheimer disease. Despite the fact that in recent years many theories about ageing have been developed, we are still far from a full understanding of the mechanisms underlying the ageing process.

Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS).

PubMed

Caserta, Stefano; Kern, Florian; Cohen, Jonathan; Drage, Stephen; Newbury, Sarah F; Llewelyn, Martin J

2016-06-20

Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these 'circulating inflammation-related microRNAs' (CIR-miRNAs) were 2.64 (IQR: 2.10-3.29) and 1.52 (IQR: 1.15-1.92) fold higher for non-infective SIRS and sepsis respectively (p < 0.0001), hence CIR-miRNAs appeared less abundant in sepsis than in SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742-0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets.

Inflamma-miRs in Aging and Breast Cancer: Are They Reliable Players?

PubMed

Cătană, Cristina Sorina; Calin, George A; Berindan-Neagoe, Ioana

2015-01-01

Human aging is characterized by chronic low-grade inflammation known as "inflammaging." Persistent low-level inflammation also plays a key role in all stages of breast cancer since "inflammaging" is the potential link between cancer and aging through NF-kB pathways highly influenced by specific miRs. Micro-RNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at a posttranscriptional level. Inflamma-miRs have been implicated in the regulation of immune and inflammatory responses. Their abnormal expression contributes to the chronic pro-inflammatory status documented in normal aging and major age-related diseases (ARDs), inflammaging being a significant mortality risk factor in both cases. Nevertheless, the correct diagnosis of inflammaging is difficult to make and its hidden contribution to negative health outcomes remains unknown. This methodological work flow was aimed at defining crucial unanswered questions about inflammaging that can be used to clarify aging-related miRNAs in serum and cell lines as well as their targets, thus confirming their role in aging and breast cancer tumorigenesis. Moreover, we aim to highlight the links between the pro-inflammatory mechanism underlying the cancer and aging processes and the precise function of certain miRNAs in cellular senescence (CS). In addition, miRNAs and cancer genes represent the basis for new therapeutic findings indicating that both cancer and ARDs genes are possible candidates involved in CS and vice versa. Our goal is to obtain a focused review that could facilitate future approaches in the investigation of the mechanisms by which miRNAs control the aging process by acting as efficient ARDs inflammatory biomarkers. An understanding of the sources and modulation of inflamma-miRs along with the identification of their specific target genes could enhance their therapeutic potential.

Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models

PubMed Central

Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

2016-01-01

Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

IL-1β induced methylation of the estrogen receptor ERα gene correlates with EMT and chemoresistance in breast cancer cells.

PubMed

Jiménez-Garduño, Aura M; Mendoza-Rodríguez, Mónica G; Urrutia-Cabrera, Daniel; Domínguez-Robles, María C; Pérez-Yépez, Eloy A; Ayala-Sumuano, Jorge Tonatiuh; Meza, Isaura

2017-08-26

Inflammation has been recently acknowledged as a key participant in the physiopathology of oncogenesis and tumor progression. The inflammatory cytokine IL-1β has been reported to induce the expression of markers associated with malignancy in breast cancerous cells through Epithelial-Mesenchymal Transition (EMT). Aggressive breast cancer tumors classified as Triple Negative do not respond to hormonal treatment because they lack three crucial receptors, one of which is the estrogen receptor alpha (ERα). Expression of ERα is then considered a good prognostic marker for tamoxifen treatment of this type of cancer, as the binding of this drug to the receptor blocks the transcriptional activity of the latter. Although it has been suggested that inflammatory cytokines in the tumor microenvironment could regulate ERα expression, the mechanism(s) involved in this process have not yet been established. We show here that, in a cell model of breast cancer cells (6D cells), in which the inflammatory cytokine IL-1β induces EMT by activation of the IL-1β/IL-1RI/β-catenin pathway, the up regulation of TWIST1 leads to methylation of the ESR1 gene promoter. This epigenetic modification produced significant decrease of the ERα receptor levels and increased resistance to tamoxifen. The direct participation of IL-1β in these processes was validated by blockage of the cytokine-induced signaling pathway by wortmannin inactivation of the effectors PI3K/AKT. These results support our previous reports that have suggested direct participation of the inflammatory cytokine IL-1β in the transition to malignancy of breast cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.

PubMed

Hahn, Rebecca T; Hoppstädter, Jessica; Hirschfelder, Kerstin; Hachenthal, Nina; Diesel, Britta; Kessler, Sonja M; Huwer, Hanno; Kiemer, Alexandra K

2014-06-01

Glucocorticoid-induced leucine zipper (GILZ) represents an anti-inflammatory mediator, whose downregulation has been described in various inflammatory processes. Aim of our study was to decipher the regulation of GILZ in vascular inflammation. Degenerated aortocoronary saphenous vein bypass grafts (n = 15), which exhibited inflammatory cell activation as determined by enhanced monocyte chemoattractrant protein 1 (MCP-1, CCL2) and Toll-like receptor 2 (TLR2) expression, showed significantly diminished GILZ protein and mRNA levels compared to healthy veins (n = 23). GILZ was also downregulated in human umbilical vein endothelial cells (HUVEC) and macrophages upon treatment with the inflammatory cytokine TNF-α in a tristetraprolin (ZFP36, TTP)- and p38 MAPK-dependent manner. To assess the functional implications of decreased GILZ expression, we determined NF-κB activation after GILZ knockdown by siRNA and found that NF-κB activity and inflammatory gene expression were significantly enhanced. Importantly, ZFP36 is induced in TNF-α-activated HUVEC as well as in degenerated vein bypasses. When atheroprotective laminar shear stress was employed, GILZ levels in HUVEC increased on mRNA and protein level. Laminar flow also counteracted TNF-α-induced ZFP36 expression and GILZ downregulation. MAP kinase phosphatase 1 (MKP-1, DUSP1), a negative regulator of ZFP36 expression, was distinctly upregulated under laminar shear stress conditions and downregulated in degenerated vein bypasses. Our data show a diminished expression of the anti-inflammatory mediator GILZ in the inflamed vasculature and indicate that GILZ downregulation requires the mRNA binding protein ZFP36. We suggest that reduced GILZ levels play a role in cardiovascular disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

PubMed

Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

2010-03-02

Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

PubMed Central

Sierra, Amanda; Beccari, Sol; Diaz-Aparicio, Irune; Encinas, Juan M.; Comeau, Samuel; Tremblay, Marie-Ève

2014-01-01

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory. PMID:24772353

Regulation of alveolar macrophage death in acute lung inflammation.

PubMed

Fan, Erica K Y; Fan, Jie

2018-03-27

Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.

Leptin, immune responses and autoimmune disease. Perspectives on the use of leptin antagonists.

PubMed

Peelman, F; Iserentant, H; Eyckerman, S; Zabeau, L; Tavernier, J

2005-01-01

The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the T(H)1 pro-inflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are T(H)1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

PubMed Central

2017-01-01

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity. PMID:28154473

Fermented non-digestible fraction from combined nixtamalized corn (Zea mays L.)/cooked common bean (Phaseolus vulgaris L.) chips modulate anti-inflammatory markers on RAW 264.7 macrophages.

PubMed

Luzardo-Ocampo, I; Campos-Vega, R; Cuellar-Nuñez, M L; Vázquez-Landaverde, P A; Mojica, L; Acosta-Gallegos, J A; Loarca-Piña, G

2018-09-01

Chronic non-communicable diseases (NCDs) are low-level inflammation processes affected by several factors including diet. It has been reported that mixed whole grain and legume consumption, e.g. corn and common bean, might be a beneficial combination due to its content of bioactive compounds. A considerable amount would be retained in the non-digestible fraction (NDF), reaching the colon, where microbiota produce short-chain fatty acids (SCFAs) and phenolic compounds (PC) with known anti-inflammatory effect. The aim of this study was to estimate the anti-inflammatory potential of fermented-NDF of corn-bean chips (FNDFC) in RAW 264.7 macrophages. After 24 h, FNDFC produced SCFAs (0.156-0.222 mmol/l), inhibited nitric oxide production > 80% and H 2 O 2  > 30%, up-regulated anti-inflammatory cytokines (I-TAC, TIMP-1) > 2-fold, and produced angiostatic and protective factors against vascular/tissue damage, and amelioration of tumor necrosis factor signalling and inflammatory bowel disease. These results confirm the anti-inflammatory potential derived from healthy corn-bean chips. Copyright © 2018. Published by Elsevier Ltd.

Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

PubMed

Lakshmi, Sowmya P; Reddy, Aravind T; Zhang, Yingze; Sciurba, Frank C; Mallampalli, Rama K; Duncan, Steven R; Reddy, Raju C

2014-03-07

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that down-regulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.

Coordination of NF-kappaB and NFAT antagonism by the forkhead transcription factor Foxd1.

PubMed

Lin, Ling; Peng, Stanford L

2006-04-15

Forkhead transcription factors play critical roles in the maintenance of immune homeostasis. In this study, we demonstrate that this regulation most likely involves intricate interactions between the forkhead family members and inflammatory transcription factors: the forkhead member Foxd1 coordinates the regulation of the activity of two key inflammatory transcription factors, NF-AT and NF-kappaB, with Foxd1 deficiency resulting in multiorgan, systemic inflammation, exaggerated Th cell-derived cytokine production, and T cell proliferation in autologous MLRs. Foxd1-deficient T cells possess increased activity of both NF-AT and NF-kappaB: the former correlates with the ability of Foxd1 to regulate casein kinase 1, an NF-AT inhibitory kinase; the latter with the ability of Foxd1 to regulate Foxj1, which regulates the NF-kappaB inhibitory subunit IkappaB beta. Thus, Foxd1 modulates inflammatory reactions and prevents autoimmunity by directly regulating anti-inflammatory regulators of the NF-AT pathway, and by coordinating the suppression of the NF-kappaB pathway via Foxj1. These findings indicate the presence of a general network of forkhead proteins that enforce T cell quiescence.

The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus

PubMed Central

Wang, Nan; Yu, Hai-Ying; Shen, Xiao-Feng; Gao, Zhi-Qin; Yang, Chun; Yang, Jian-Jun

2015-01-01

Objectives. Active inflammatory responses play an important role in the pathogenesis of depression. We hypothesized that the rapid antidepressant effect of ketamine is associated with the down-regulation of pro-inflammatory mediators. Methods. Forty-eight rats were equally randomized into six groups (a control and five chronic unpredictable mild stress (CUMS) groups) and given either saline or 10 mg/kg ketamine, respectively. The forced swimming test was performed, and the hippocampus was subsequently harvested for the determination of levels of interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α), indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), and tryptophan (TRP). Results. CUMS induced depression-like behaviours and up-regulated the hippocampal levels of IL-1β, IL-6, TNF-α, IDO, and the KYN/TRP ratio, which were attenuated by a sub-anaesthetic dose of ketamine. Conclusion. CUMS-induced depression-like behaviours are associated with a reduction in hippocampal inflammatory mediators, whereas ketamine’s antidepressant effect is associated with a down-regulation of pro-inflammatory cytokines in the rat hippocampus. PMID:26220286

A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease.

PubMed

Zhong, Hai-Jing; Wang, Wanhe; Kang, Tian-Shu; Yan, Hui; Yang, Yali; Xu, Lipeng; Wang, Yuqiang; Ma, Dik-Lung; Leung, Chung-Hang

2017-01-12

We report herein the identification of the rhodium(III) complex [Rh(phq) 2 (MOPIP)] + (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.

Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges

PubMed Central

Saxena, Amit; Russo, Ilaria; Frangogiannis, Nikolaos G

2015-01-01

In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair and remodeling of the infarcted heart. Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin (IL)-1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes, by stimulating chemokine and adhesion molecule expression. Distinct chemokine/chemokine receptor pairs are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. Over the last 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations, in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury, or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review manuscript discusses the biology of the inflammatory response following myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction. PMID:26241027

Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis.

PubMed

Booty, Matthew G; Nunes-Alves, Cláudio; Carpenter, Stephen M; Jayaraman, Pushpa; Behar, Samuel M

2016-02-15

The differentiation of effector CD8(+) T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. In this study, we define three signals regulating CD8(+) T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12, type I IFN, and IL-27. Using mixed bone marrow chimeras, we compared wild-type and cytokine receptor knockout CD8(+) T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks postinfection, IL-12, type 1 IFN, and IL-27 were all required for efficient CD8(+) T cell expansion in the lungs. We next determined if these cytokines directly promote CD8(+) T cell priming or are required only for expansion in the lungs. Using retrogenic CD8(+) T cells specific for the M. tuberculosis Ag TB10.4 (EsxH), we observed that IL-12 is the dominant cytokine driving both CD8(+) T cell priming in the lymph node and expansion in the lungs; however, type I IFN and IL-27 have nonredundant roles supporting pulmonary CD8(+) T cell expansion. Thus, IL-12 is a major signal promoting priming in the lymph node, but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore, these cytokines regulate the differentiation and function of CD8(+) T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8(+) T cell regulation during tuberculosis. Copyright © 2016 by The American Association of Immunologists, Inc.

Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications.

PubMed

Cohen-Cymberknoh, Malena; Kerem, Eitan; Ferkol, Thomas; Elizur, Arnon

2013-12-01

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger 'cell stress' and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.

Glucocorticoids and estrogens modulate the NF-κB pathway differently in the micro- and macrovasculature.

PubMed

Edgar, Abarca-Rojano; Judith, Pacheco-Yépez; Elisa, Drago-Serrano Maria; Rafael, Campos-Rodríguez

2013-12-01

Estrogens and glucocorticoids have synergistic effects in the micro and macrovasculature of endothelial cells (ECs), having pro-inflammatory effects in the former and inhibiting the expression of adhesion molecules in the latter. The molecular basis of these effects in the endothelium has not yet been clarified. We postulate that the ECs of the micro- and macrovasculature have different non-genomic mechanisms that regulate levels of preexisting complexes of glucocorticoids and estrogens with their respective receptors. Since these receptors are regulated by NF-κB, their expression could be critical to the activation of a pro- or anti-inflammatory response. In the macrovasculature the synergistic effects of estrogens and glucocorticoids on ECs may be through the inhibition of NF-κB, leading to the inhibition of the expression of inflammatory molecules. It seems likely that glucocorticoid-receptor and estrogen-receptor complexes directly bind to NF-κB proteins in the macrovasculature, resulting in the inhibition of an excessive proinflammatory response. Further insights into these processes may help clarify the role of the endothelial cells of different vascular beds during the inflammatory response and chronic inflammation, and thus contribute to the design of more effective therapeutic strategies for the prevention of diseases related to inflammation, including atherosclerosis, systemic lupus erythematosus and rheumatoid arthritis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways

PubMed Central

Manteiga, Sara; Lee, Kyongbum

2016-01-01

Background: A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals’ effects on adult adipose tissue. Objectives: Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. Methods: We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Results: Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor’s activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Conclusions: Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ. Citation: Manteiga S, Lee K. 2017. Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways. Environ Health Perspect 125:615–622; http://dx.doi.org/10.1289/EHP464 PMID:27384973

Sleep, immunity and inflammation in gastrointestinal disorders.

PubMed

Ali, Tauseef; Choe, James; Awab, Ahmed; Wagener, Theodore L; Orr, William C

2013-12-28

Sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many research endeavors. An estimated 70 million Americans suffer from some form of sleep disorder. Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability, slower response times and performance detriments. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. Several research studies support the associations among sleep, immune function and inflammation. Here, we review the current research linking sleep, immune function, and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders. Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep. The inflammatory cytokines such as tumor necrosis factor, interleukin-1 (IL-1), and IL-6 have been shown to be a significant contributor of sleep disturbances. On the other hand, sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines. Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease, gastro-esophageal reflux, liver disorders and colorectal cancer. In turn, abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases. Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients.

Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2 mediated PGE2 production

PubMed Central

Ranganathan, Punithavathi Vilapakkam; Jayakumar, Calpurnia; Mohamed, Riyaz; Dong, Zheng; Ramesh, Ganesan

2012-01-01

Netrin-1 regulates inflammation but the mechanism by which this occurs is unknown. Here we explore the role of netrin-1 in regulating the production of the prostanoid metabolite PGE2 from neutrophils in in vitro and in vivo disease models. Ischemia reperfusion in wild-type and RAG-1 knockout mice induced severe kidney injury that was associated with a large increase in neutrophil infiltration and COX-2 expression in the infiltrating leukocytes. Administration of netrin-1 suppressed COX-2 expression, PGE2 and thromboxane production, and neutrophil infiltration into the kidney. This was associated with reduced apoptosis, inflammatory cytokine and chemokine expression, and improved kidney function. Treatment with the PGE2 receptor EP4 agonist enhanced neutrophil infiltration and renal injury which was not inhibited by netrin-1. Consistent with in vivo data, both LPS and IFNγ-induced inflammatory cytokine production in macrophages and IL-17-induced IFNγ production in neutrophils were suppressed by netrin-1 in vitro by suppression of COX-2 expression. Moreover, netrin-1 regulates COX-2 expression at the transcriptional level through the regulation of NFκB activation. Thus, netrin-1 regulates the inflammatory response of neutrophils and macrophages through suppression of COX-2 mediated PGE2 production. This could be a potential drug for treating many inflammatory immune disorders. PMID:23447066

Baicalin inhibits toll-like receptor 2/4 expression and downstream signaling in rat experimental periodontitis.

PubMed

Sun, Jun-Yi; Li, Dong-Ling; Dong, Yan; Zhu, Chun-Hui; Liu, Jin; Li, Jue-Dan; Zhou, Tao; Gou, Jian-Zhong; Li, Ang; Zang, Wei-Jin

2016-07-01

Periodontitis is a severe inflammatory response, leading to characteristic periodontal soft tissue destruction and alveolar bone resorption. Baicalin possesses potent anti-inflammatory activity; however, it is still unclear whether baicalin regulates toll-like receptor (TLR) 2/4 expression and downstream signaling during the process of periodontitis. In this study, the cervical area of the maxillary second molars of rats was ligated and inoculated with Porphyromonas gingivalis (P. gingivalis) for 4weeks to induce periodontitis. Some rats with periodontitis were treated intragastrically with baicalin (50, 100 or 200mg/kg/day) or vehicle for 4weeks. Compared with the sham group, the levels of TLR2, TLR4 and MyD88 expression and the p38 MAPK and NF-κB activation were up-regulated in the experimental periodontitis group (EPG), accompanied by marked alveolar bone loss and severe inflammation. Treatment with 100 or 200mg/kg/day baicalin dramatically reduced the alveolar bone loss, the levels of HMGB1, TNF-α, IL-1β, and MPO expression, and the numbers of inflammatory infiltrates in the gingival tissues. Importantly, treatment with 100 or 200mg/kg/day baicalin mitigated the periodontitis-up-regulated TLR2, TLR4 and MyD88 expression, and the p38 MAPK and NF-κB activation. Hence, the blockage of the TLR2 and TLR4/MyD88/p38 MAPK/NF-κB signaling by baicalin may contribute to its anti-inflammatory effects in rat model of periodontitis. In conclusion, these novel findings indicate that baicalin inhibits the TLR2 and TLR4 expression and the downstream signaling and mitigates inflammatory responses and the alveolar bone loss in rat experimental periodontitis. Therefore, baicalin may be a potential therapeutic agent for treatment of periodontitis. Copyright © 2016 Elsevier B.V. All rights reserved.

Synergistic regulation of the acute phase protein SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines.

PubMed

Liu, Quan-Sheng; Nilsen-Hamilton, Marit; Xiong, Si-Dong

2003-10-25

SIP24/24p3 is a secreted murine acute phase protein which has been speculated to play an anti-inflammatory role in vivo. Recently SIP24/24p3 has been found to be able to specifically induce apoptosis in leukocytes. By using (35)S metabolic labeling method, we studied the regulation of SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines IL-6 and TNF-alpha in cultured Balb/c 3T3 and BNL cells. The following results were observed: (1) dexamethasone induced the expression of SIP24/24p3 in both Balb/c 3T3 and BNL cells, the induction was more significant in BNL cells; (2) dexamethasone and IL-6 synergistically induced the expression of SIP24/24p3 in both Balb/c 3T3 and BNL cells; (3) in Balb/c 3T3 cells dexamethasone and TNF-alpha acted synergistically to induce the expression of SIP24/24p3, whereas in BNL cells dexamethasone and TNF-alpha induced the expression of SIP24/24p3 in an additive manner; (4) dexamethasone and IL-6/TNF-alpha acted synergistically in Balb/c 3T3 cells and additively in BNL cells to induce the expression of SIP24/24p3. The inducibility of SIP24/24p3 by multiple factors will help to explain its highly specific expression in vivo. The difference in the expression patterns of SIP24/24p3 in different cell types is also suggestive to its expression and regulation in hepatic and extrahepatic tissues. Finally, the fact that SIP24/24p3 protein can be induced by both pro-inflammatory as well as anti-inflammatory factors is indicative of the important role of SIP24/24p3 in the entire acute phase response process.

Gastrin-releasing peptide induces monocyte adhesion to vascular endothelium by upregulating endothelial adhesion molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Mi-Kyoung; Park, Hyun-Joo; Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 626-870

Gastrin-releasing peptide (GRP) is a neuropeptide that plays roles in various pathophysiological conditions including inflammatory diseases in peripheral tissues; however, little is known about whether GRP can directly regulate endothelial inflammatory processes. In this study, we showed that GRP promotes the adhesion of leukocytes to human umbilical vein endothelial cells (HUVECs) and the aortic endothelium. GRP increased the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by activating nuclear factor-κB (NF-κB) in endothelial cells. In addition, GRP activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38MAPK, and AKT, and the inhibition of these signaling pathways significantly reduced GRP-inducedmore » monocyte adhesion to the endothelium. Overall, our results suggested that GRP may cause endothelial dysfunction, which could be of particular relevance in the development of vascular inflammatory disorders. - Highlights: • GRP induces adhesion of monocytes to vascular endothelium. • GRP increases the expression of endothelial adhesion molecules through the activation of NF-κB. • ERK1/2, p38MAPK, and Akt pathways are involved in the GRP-induced leukocyte adhesiveness to endothelium.« less

LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.

PubMed

Alexandre-Moreira, Magna S; Takiya, Christina M; de Arruda, Luciana B; Pascarelli, Bernardo; Gomes, Raquel N; Castro Faria Neto, Hugo C; Lima, Lídia M; Barreiro, Eliezer J

2005-03-01

As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.

The targeted delivery of the c-Src peptide complexed with schizophyllan to macrophages inhibits polymicrobial sepsis and ulcerative colitis in mice.

PubMed

Kim, Ye-Ram; Hwang, Jangsun; Koh, Hyun-Jung; Jang, Kiseok; Lee, Jong-Dae; Choi, Jonghoon; Yang, Chul-Su

2016-05-01

Hyper-inflammatory responses triggered by intracellular reactive oxygen species (ROS) can lead to a variety of diseases, including sepsis and colitis. However, the regulators of this process remain poorly defined. In this study, we demonstrate that c-Src is a negative regulator of cellular ROS generation through its binding to p47phox. This molecule also competitively inhibits the NADPH oxidase complex (NOX) assembly. Furthermore, we developed the schizophyllan (SPG)-c-Src SH3 peptide, which is a β-1,3-glucan conjugated c-Src SH3-derived peptide composed of amino acids 91-108 and 121-140 of c-Src. The SPG-SH3 peptide has a significant therapeutic effect on mouse ROS-mediated inflammatory disease models, cecal-ligation-puncture-induced sepsis, and dextran sodium sulfate-induced colitis. It does so by inhibiting the NOX subunit assembly and proinflammatory mediator production. Therefore, the SPG-SH3 peptide is a potential therapeutic agent for ROS-associated lethal inflammatory diseases. Our findings provide clues for the development of new peptide-base drugs that will target p47phox. Copyright © 2016 Elsevier Ltd. All rights reserved.

Necroptosis: a potential, promising target and switch in acute pancreatitis.

PubMed

Wang, Gang; Qu, Feng-Zhi; Li, Le; Lv, Jia-Chen; Sun, Bei

2016-02-01

Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its progression and prognosis. During AP, acinar cells undergo two major modes of death, including necrosis and apoptosis. Acinar necrosis can lead to intensely local and systemic inflammatory responses, which both induce and aggravate the lesion. Necrosis has long been considered an unregulated, and passive cell death process. Since the effective interventions of necrosis are difficult to perform, its relevant studies have not received adequate attention. Necroptosis is a newly discovered cell death modality characterized by both necrosis and apoptosis, i.e., it is actively regulated by special genes, while has the typical morphological features of necrosis. Currently, necroptosis is gradually becoming an important topic in the fields of inflammatory diseases. The preliminary results from necroptosis in AP have confirmed the existence of acinar cell necroptosis, which may be a potential target for effectively regulating inflammatory injuries and improving its outcomes; however, the functional changes and mechanisms of necroptosis still require further investigation. This article reviewed the progress of necroptosis in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets.

Neuro-immune interactions in inflammation and host defense: Implications for transplantation.

PubMed

Chavan, Sangeeta S; Ma, Pingchuan; Chiu, Isaac M

2018-03-01

Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Leptin in the interplay of inflammation, metabolism and immune system disorders.

PubMed

Abella, Vanessa; Scotece, Morena; Conde, Javier; Pino, Jesús; Gonzalez-Gay, Miguel Angel; Gómez-Reino, Juan J; Mera, Antonio; Lago, Francisca; Gómez, Rodolfo; Gualillo, Oreste

2017-02-01

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages

PubMed Central

Luheshi, Nadia M; Giles, James A; Lopez-Castejon, Gloria; Brough, David

2012-01-01

Abstract Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1β secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1β from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1β release. IL-1β release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation. PMID:22105559

RIG-I Like Receptors and Their Signaling Crosstalk in the Regulation of Antiviral Immunity

PubMed Central

Ramos, Hilario J; Gale, Michael

2011-01-01

During virus infection, multiple immune signaling pathways are triggered, both within the host cell and bystander cells of an infected tissue. These pathways act in concert to mediate innate antiviral immunity and to initiate the inflammatory response against infection. The RIG-I-like receptor (RLR) family of pattern recognition receptors (PRRs) is a group of cytosolic RNA helicase proteins that can identify viral RNA as nonself via binding to pathogen associated molecular patter (PAMP) motifs within RNA ligands that accumulate during virus infection. This interaction then leads to triggering of an innate antiviral response within the infected cells through RLR induction of downstream effector molecules such as type I interferon (IFN) and other pro-inflammatory cytokines that serve to induce antiviral and inflammatory gene expression within the local tissue. Cellular regulation of RLR signaling is a critical process that can direct the outcome of infection and is essential for governance of the overall immune response and avoidance of immune toxicity. Mechanisms of positive and negative regulation of RLR signaling have been identified that include signaling crosstalk between RLR pathways and Nuclear Oligomerization Domain (NOD)-Like Receptor (NLR) pathways and Caspase networks. Furthermore, many viruses have evolved mechanisms to target these pathways to promote enhanced replication and spread within the host. These virus-host interactions therefore carry important consequences for host immunity and viral pathogenesis. Understanding the pivotal role of RLRs in immune regulation and signaling crosstalk in antiviral immunity may provide new insights into therapeutic strategies for the control of virus infection and immunity. PMID:21949557

Regulation of the clock gene expression in human adipose tissue by weight loss.

PubMed

Pivovarova, O; Gögebakan, Ö; Sucher, S; Groth, J; Murahovschi, V; Kessler, K; Osterhoff, M; Rudovich, N; Kramer, A; Pfeiffer, A F H

2016-06-01

The circadian clock coordinates numerous metabolic processes to adapt physiological responses to light-dark and feeding regimens and is itself regulated by metabolic cues. The implication of the circadian clock in the regulation of energy balance and body weight is widely studied in rodents but not in humans. Here we investigated (1) whether the expression of clock genes in human adipose tissue is changed by weight loss and (2) whether these alterations are associated with metabolic parameters. Subcutaneous adipose tissue (SAT) samples were collected before and after 8 weeks of weight loss on an 800 kcal per day hypocaloric diet (plus 200 g per day vegetables) at the same time of the day. Fifty overweight subjects who lost at least 8% weight after 8 weeks were selected for the study. The expression of 10 clock genes and key metabolic and inflammatory genes in adipose tissue was determined by quantitative real-time PCR. The expression of core clock genes PER2 and NR1D1 was increased after the weight loss. Correlations of PERIOD expression with body mass index (BMI) and serum total, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol levels and of NR1D1 expression with total and LDL cholesterol were found that became non-significant after correction for multiple testing. Clock gene expression levels and their weight loss-induced changes tightly correlated with each other and with genes involved in fat metabolism (FASN, CPT1A, LPL, PPARG, PGC1A, ADIPOQ), energy metabolism (SIRT1), autophagy (LC3A, LC3B) and inflammatory response (NFKB1, NFKBIA, NLRP3, EMR1). Clock gene expression in human SAT is regulated by body weight changes and associated with BMI, serum cholesterol levels and the expression of metabolic and inflammatory genes. Our data confirm the tight crosstalk between molecular clock and metabolic and inflammatory pathways involved in adapting adipose tissue metabolism to changes of the energy intake in humans.

Retinoic acid receptor-related orphan receptor α stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress.

PubMed

Liu, Yin; Chen, Yulong; Zhang, Jinlong; Liu, Yulan; Zhang, Yanjie; Su, Zhiguang

2017-08-25

Adipose tissue inflammation has been linked to metabolic diseases such as obesity and type 2 diabetes. However, the molecules that mediate inflammation in adipose tissue have not been addressed. Although retinoic acid receptor-related orphan receptor α (RORα) is known to be involved in the regulation of inflammatory response in some tissues, its role is largely unknown in adipose tissue. Conversely, it is known that endoplasmic reticulum (ER) stress and unfolding protein response (UPR) signaling affect the inflammatory response in obese adipose tissue, but whether RORα regulates these processes remains unknown. In this study, we investigate the link between RORα and adipose tissue inflammation. We showed that the inflammatory response in macrophages or 3T3-L1 adipocytes stimulated by lipopolysaccharide, as well as adipose tissue in obese mice, markedly increased the expression of RORα. Adenovirus-mediated overexpression of RORα or treatment with the RORα-specific agonist SR1078 enhanced the expression of inflammatory cytokines and increased the number of infiltrated macrophages into adipose tissue. Furthermore, SR1078 up-regulated the mRNA expression of ER stress response genes and enhanced phosphorylations of two of the three mediators of major UPR signaling pathways, PERK and IRE1α. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of RORα induced inflammation in adipose tissue. Our data suggest that RORα-induced ER stress response potentially contributes to the adipose tissue inflammation that can be mitigated by treatment with chemical chaperones. The relationships established here between RORα expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse

PubMed Central

Rayes, Julie; Wichaiyo, Surasak; Haining, Elizabeth J.; Lowe, Kate; Grygielska, Beata; Laloo, Ryan; Flodby, Per; Borok, Zea; Crandall, Edward D.; Thickett, David R.; Watson, Steve P.

2017-01-01

There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS. PMID:28839100

[Association of Some Homozygous Genotypes of Genes Regulating Inflammation, Destruction and Angiogenesis With Laboratory Markers of Atherosclerosis Course in Men With Stable Effort Angina].

PubMed

Shevchenko, A V; Konenkov, V I; Prokofiev, V F; Ragino, Yu I; Chernjavski, A M; Voevoda, M I

2016-03-01

Great number of factors stimulating or inhibiting production of proteins in inflammatory process influence serum levels of markers of inflammation. A number of homozygous genotypes of inflammation, destruction, and angiogenesis genes have been found to be associated with basic clinical-laboratory indices of inflammation and atherosclerotic process. The revealed genetic markers can be used as complimentary markers of prognosis of the disease course.

MicroRNA-132 enhances transition from inflammation to proliferation during wound healing

PubMed Central

Li, Dongqing; Wang, Aoxue; Liu, Xi; Meisgen, Florian; Grünler, Jacob; Botusan, Ileana R.; Narayanan, Sampath; Erikci, Erdem; Li, Xi; Blomqvist, Lennart; Du, Lei; Pivarcsi, Andor; Sonkoly, Enikö; Chowdhury, Kamal; Catrina, Sergiu-Bogdan; Ståhle, Mona; Landén, Ning Xu

2015-01-01

Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-β1 and TGF-β2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response– and cell cycle–related genes. In keratinocytes, miR-132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-κB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase. PMID:26121747

Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model.

PubMed

Giangreco, Angeline A; Dambal, Shweta; Wagner, Dennis; Van der Kwast, Theodorus; Vieth, Reinhold; Prins, Gail S; Nonn, Larisa

2015-04-01

Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal-epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-α, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro-inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, the prostatic epithelium appears to be the main producer of 1,25(OH)2D. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma-epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland. Copyright © 2014 Elsevier Ltd. All rights reserved.

"TRP inflammation" relationship in cardiovascular system.

PubMed

Numata, Tomohiro; Takahashi, Kiriko; Inoue, Ryuji

2016-05-01

Despite considerable advances in the research and treatment, the precise relationship between inflammation and cardiovascular (CV) disease remains incompletely understood. Therefore, understanding the immunoinflammatory processes underlying the initiation, progression, and exacerbation of many cardiovascular diseases is of prime importance. The innate immune system has an ancient origin and is well conserved across species. Its activation occurs in response to pathogens or tissue injury. Recent studies suggest that altered ionic balance, and production of noxious gaseous mediators link to immune and inflammatory responses with altered ion channel expression and function. Among plausible candidates for this are transient receptor potential (TRP) channels that function as polymodal sensors and scaffolding proteins involved in many physiological and pathological processes. In this review, we will first focus on the relevance of TRP channel to both exogenous and endogenous factors related to innate immune response and transcription factors related to sustained inflammatory status. The emerging role of inflammasome to regulate innate immunity and its possible connection to TRP channels will also be discussed. Secondly, we will discuss about the linkage of TRP channels to inflammatory CV diseases, from a viewpoint of inflammation in a general sense which is not restricted to the innate immunity. These knowledge may serve to provide new insights into the pathogenesis of various inflammatory CV diseases and their novel therapeutic strategies.

Effects of Inflammation on Multiscale Biomechanical Properties of Cartilaginous Cells and Tissues

PubMed Central

2017-01-01

Cells within cartilaginous tissues are mechanosensitive and thus require mechanical loading for regulation of tissue homeostasis and metabolism. Mechanical loading plays critical roles in cell differentiation, proliferation, biosynthesis, and homeostasis. Inflammation is an important event occurring during multiple processes, such as aging, injury, and disease. Inflammation has significant effects on biological processes as well as mechanical function of cells and tissues. These effects are highly dependent on cell/tissue type, timing, and magnitude. In this review, we summarize key findings pertaining to effects of inflammation on multiscale mechanical properties at subcellular, cellular, and tissue level in cartilaginous tissues, including alterations in mechanotransduction and mechanosensitivity. The emphasis is on articular cartilage and the intervertebral disc, which are impacted by inflammatory insults during degenerative conditions such as osteoarthritis, joint pain, and back pain. To recapitulate the pro-inflammatory cascades that occur in vivo, different inflammatory stimuli have been used for in vitro and in situ studies, including tumor necrosis factor (TNF), various interleukins (IL), and lipopolysaccharide (LPS). Therefore, this review will focus on the effects of these stimuli because they are the best studied pro-inflammatory cytokines in cartilaginous tissues. Understanding the current state of the field of inflammation and cell/tissue biomechanics may potentially identify future directions for novel and translational therapeutics with multiscale biomechanical considerations. PMID:29152560

Surgical inflammatory stress: the embryo takes hold of the reins again

PubMed Central

2013-01-01

The surgical inflammatory response can be a type of high-grade acute stress response associated with an increasingly complex trophic functional system for using oxygen. This systemic neuro-immune-endocrine response seems to induce the re-expression of 2 extraembryonic-like functional axes, i.e. coelomic-amniotic and trophoblastic-yolk-sac-related, within injured tissues and organs, thus favoring their re-development. Accordingly, through the up-regulation of two systemic inflammatory phenotypes, i.e. neurogenic and immune-related, a gestational-like response using embryonic functions would be induced in the patient’s injured tissues and organs, which would therefore result in their repair. Here we establish a comparison between the pathophysiological mechanisms that are produced during the inflammatory response and the physiological mechanisms that are expressed during early embryonic development. In this way, surgical inflammation could be a high-grade stress response whose pathophysiological mechanisms would be based on the recapitulation of ontogenic and phylogenetic-related functions. Thus, the ultimate objective of surgical inflammation, as a gestational process, is creating new tissues/organs for repairing the injured ones. Since surgical inflammation and early embryonic development share common production mechanisms, the factors that hamper the wound healing reaction in surgical patients could be similar to those that impair the gestational process. PMID:23374964

Effects of Inflammation on Multiscale Biomechanical Properties of Cartilaginous Cells and Tissues.

PubMed

Nguyen, Q T; Jacobsen, T D; Chahine, N O

2017-11-13

Cells within cartilaginous tissues are mechanosensitive and thus require mechanical loading for regulation of tissue homeostasis and metabolism. Mechanical loading plays critical roles in cell differentiation, proliferation, biosynthesis, and homeostasis. Inflammation is an important event occurring during multiple processes, such as aging, injury, and disease. Inflammation has significant effects on biological processes as well as mechanical function of cells and tissues. These effects are highly dependent on cell/tissue type, timing, and magnitude. In this review, we summarize key findings pertaining to effects of inflammation on multiscale mechanical properties at subcellular, cellular, and tissue level in cartilaginous tissues, including alterations in mechanotransduction and mechanosensitivity. The emphasis is on articular cartilage and the intervertebral disc, which are impacted by inflammatory insults during degenerative conditions such as osteoarthritis, joint pain, and back pain. To recapitulate the pro-inflammatory cascades that occur in vivo, different inflammatory stimuli have been used for in vitro and in situ studies, including tumor necrosis factor (TNF), various interleukins (IL), and lipopolysaccharide (LPS). Therefore, this review will focus on the effects of these stimuli because they are the best studied pro-inflammatory cytokines in cartilaginous tissues. Understanding the current state of the field of inflammation and cell/tissue biomechanics may potentially identify future directions for novel and translational therapeutics with multiscale biomechanical considerations.

Down-regulation of IL-8 by high-dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1

PubMed Central

Dauletbaev, N; Herscovitch, K; Das, M; Chen, H; Bernier, J; Matouk, E; Bérubé, J; Rousseau, S; Lands, L C

2015-01-01

Background and Purpose There is current interest in vitamin D as a potential anti-inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up-regulates the anti-inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL-8. IL-8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down-regulate IL-8 production in CF macrophages. Experimental Approach CF and healthy monocyte-derived macrophages (MDM) were treated with two vitamin D metabolites, 25-hydroxyvitamin D3 (25OHD3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or paricalcitol, synthetic analogue of 1,25(OH)2D3. 25OHD3 was tested at doses of 25–150 nM, whereas 1,25(OH)2D3 and paricalcitol at doses of up to 100 nM. IL-8 was stimulated by bacterial virulence factors. As potential anti-inflammatory mechanism of vitamin D metabolites, we assessed up-regulation of DUSP1. Key Results MDM from patients with CF and some healthy donors showed excessive production of stimulated IL-8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down-regulated stimulated IL-8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3, or >1 nM for 1,25(OH)2D3 and paricalcitol). The magnitude of IL-8 down-regulation by vitamin D metabolites or paricalcitol was moderate (∼30% vs. >70% by low-dose dexamethasone). Transcriptional up-regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL-8 down-regulation. Conclusions and Implications Vitamin D metabolites and their analogues moderately down-regulate IL-8 in hyperinflammatory macrophages, including those from CF. This down-regulation appears to go through DUSP1-independent mechanisms. PMID:26178144

Down-regulation of IL-8 by high-dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1.

PubMed

Dauletbaev, N; Herscovitch, K; Das, M; Chen, H; Bernier, J; Matouk, E; Bérubé, J; Rousseau, S; Lands, L C

2015-10-01

There is current interest in vitamin D as a potential anti-inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up-regulates the anti-inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL-8. IL-8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down-regulate IL-8 production in CF macrophages. CF and healthy monocyte-derived macrophages (MDM) were treated with two vitamin D metabolites, 25-hydroxyvitamin D3 (25OHD3 ) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), or paricalcitol, synthetic analogue of 1,25(OH)2 D3 . 25OHD3 was tested at doses of 25-150 nM, whereas 1,25(OH)2 D3 and paricalcitol at doses of up to 100 nM. IL-8 was stimulated by bacterial virulence factors. As potential anti-inflammatory mechanism of vitamin D metabolites, we assessed up-regulation of DUSP1. MDM from patients with CF and some healthy donors showed excessive production of stimulated IL-8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down-regulated stimulated IL-8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3 , or >1 nM for 1,25(OH)2 D3 and paricalcitol). The magnitude of IL-8 down-regulation by vitamin D metabolites or paricalcitol was moderate (∼30% vs. >70% by low-dose dexamethasone). Transcriptional up-regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL-8 down-regulation. Vitamin D metabolites and their analogues moderately down-regulate IL-8 in hyperinflammatory macrophages, including those from CF. This down-regulation appears to go through DUSP1-independent mechanisms. © 2015 The British Pharmacological Society.

Sinomenine inhibits lipopolysaccharide-induced inflammatory injury by regulation of miR-101/MKP-1/JNK pathway in keratinocyte cells.

PubMed

Liu, Shumei; Man, Yigang; Zhao, Li

2018-05-01

Recent studies have demonstrated that Sinomenine (SIN) exerted anti-inflammatory effect in various immune-related diseases. However, the effect of SIN on glucocorticoids dermatitis has not been investigated. In our study, we aimed to explore the effect of SIN on lipopolysaccharide (LPS)-induced inflammatory injury in HaCaT cells. We constructed an inflammatory injury model of LPS-induced HaCaT cells, then SIN was added to LPS-treated cells, cell viability, apoptosis, apoptosis-associated factors and inflammatory cytokines were detected by CCK-8, flow cytometry, western blot, qRT-PCR and ELISA. Subsequently, miR-101 mimic and mimic control were transfected into HaCaT cells to investigate the effect of SIN and miR-101 on LPS-induced cells injury. Furthermore, MKP-1 and JNK signal pathways were measured by qRT-PCR and western blot. Finally, the animal experiment was performed to further clarify the effect of SIN on inflammatoty injury. LPS suppressed cell viability, promoted apoptosis and increased IL-6, IL-8 and TNF-α expressions and secretions in HaCaT cells. SIN significantly alleviated LPS-induced HaCaT cells injury. Additionally, SIN down-regulated miR-101 expression, and the protective effect of SIN on LPS-induced inflammatory injury was abolished by miR-101 overexpression. Besides, SIN promoted MKP-1 expression by down-regulation of miR-101, and SIN inhibited JNK signal pathway by up-regulation of MKP-1 expression in LPS-treated HaCaT cells. Animal experiments revealed that SIN exhibited anti-inflammatory effects in vivo. The data indicated that SIN attenuated LPS-induced inflammatory injury by regulation of miR-101, MKP-1 and JNK pathway. These findings might provide a novel method for treatment of glucocorticoids dermatitis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity.

PubMed

Patterson, Susan L

2015-09-01

Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain's resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro-inflammatory cytokines (e.g. interleukin-1beta or IL-1β) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1β is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1β on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain-derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by infection or injury, and it plays a critical role in many of the same memory and hippocampal plasticity processes compromised by dysregulated production of IL-1β. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd. All rights reserved.

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT

NASA Astrophysics Data System (ADS)

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-07-01

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT.

PubMed

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-07-16

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

PubMed Central

2014-01-01

Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism. PMID:25152696

Phosphodiesterases regulate airway smooth muscle function in health and disease.

PubMed

Krymskaya, Vera P; Panettieri, Reynold A

2007-01-01

On the basis of structure, regulation, and kinetic properties, phosphodiesterases (PDEs) represent a superfamily of enzymes divided into 11 subfamilies that catalyze cytosolic levels of 3',5'-cyclic adenosine monophosphate (cAMP) or 3',5'-cyclic guanosine monophosphate (cGMP) to 5'-AMP or 5'-GMP, respectively. PDE4 represents the major PDE expressed in inflammatory cells as well as airway smooth muscle (ASM), and selective PDE4 inhibitors provide a broad spectrum of anti-inflammatory effects such as abrogating cytokine and chemokine release from inflammatory cells and inhibiting inflammatory cell trafficking. Due to cell- and tissue-specific gene expression and regulation, PDEs modulate unique organ-based functions. New tools or compounds that selectively inhibit PDE subfamilies and genetically engineered mice deficient in selective isoforms have greatly enhanced our understanding of PDE function in airway inflammation and resident cell function. This chapter will focus on recent advances in our understanding of the role of PDE in regulating ASM function.

Bioactive interleukin-1alpha is cytolytically released from Candida albicans-infected oral epithelial cells.

PubMed

Dongari-Bagtzoglou, A; Kashleva, H; Villar, C Cunha

2004-12-01

Oral epithelial cells are primary targets of Candida albicans in the oropharynx and may regulate the inflammatory host response to this pathogen. This investigation studied the mechanisms underlying interleukin-1alpha (IL-1alpha) release by oral epithelial cells and the role of IL-1alpha in regulating the mucosal inflammatory response to C. albicans. Infected oral epithelial cells released processed IL-1alpha protein in culture supernatants. The IL-1alpha generated was stored intracellularly and was released upon cell lysis. This was further supported by the fact that different C. albicans strains induced variable IL-1alpha release, depending on their cytolytic activity. IL-1alpha from C. albicans-infected oral epithelial cells upregulated proinflammatory cytokine secretion (IL-8 and GM-CSF) in uninfected oral epithelial or stromal cells. Our studies suggest that production of IL-1alpha, IL-8 and GM-CSF may take place in the oral mucosa in response to lytic infection of epithelial cells with C. albicans. This process can act as an early innate immune surveillance system and may contribute to the clinicopathologic signs of infection in the oral mucosa.

SENESCENCE (AGEING) @ 2011

PubMed Central

Nigam, Anjana

2011-01-01

Ageing, also called as senescence, is one of the most complex, intrinsic, biological processes of growing older and resulting into reduced functional ability of the organism. Telomerase, environment, low calorie diets, free radicals, etc., are all believed to affect this ageing process. A number of genetic components of ageing have been identified using model organisms. Genes, mainly the sirtuins, regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses. In higher organisms, ageing is likely to be regulated, in part, through the insulin/insulin-like growth factor 1 pathway. Besides this, the induction of apoptosis in stem and progenitor cells, increased p53 activity, and autophagy is also thought to trigger premature organismal ageing. Ageing has also been shown to upregulate expression of inflammatory mediators in mouse adipose tissue. The understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti-ageing medicine for targeted therapy. Future research areas must include targeted role of systemic inflammatory markers such as C-reactive protein and interleukin 6 and other biochemical and genetic studies including gene signaling pathways, gene microarray analysis, gene modulation, gene therapy, and development of animal/human models for potential therapeutic measures and evaluations. PMID:22345758

A Potential Contribution of Chemokine Network Dysfunction to the Depressive Disorders

PubMed Central

Ślusarczyk, Joanna; Trojan, Ewa; Chwastek, Jakub; Głombik, Katarzyna; Basta-Kaim, Agnieszka

2016-01-01

In spite of many years of research, the pathomechanism of depression has not yet been elucidated. Among many hypotheses, the immune theory has generated a substantial interest. Up till now, it has been thought that depression is accompanied by the activation of inflammatory response and increase in pro-inflammatory cytokine levels. However, recently this view has become controversial, mainly due to the family of small proteins called chemokines. They play a key role in the modulation of peripheral function of the immune system by controlling immune reactions, mediating immune cell communication, and regulating chemotaxis and cell adhesion. Last studies underline significance of chemokines in the central nervous system, not only in the neuromodulation but also in the regulation of neurodevelopmental processes, neuroendocrine functions and in mediating the action of classical neurotransmitters. Moreover, it was demonstrated that these proteins are responsible for maintaining interactions between neuronal and glial cells both in the developing and adult brain also in the course of diseases. This review outlines the role of chemokine in the central nervous system under physiological and pathological conditions and their involvement in processes underlying depressive disorder. It summarizes the most important data from experimental and clinical studies. PMID:26893168

Curcumin as a natural regulator of monocyte chemoattractant protein-1.

PubMed

Karimian, Maryam Saberi; Pirro, Matteo; Majeed, Muhammed; Sahebkar, Amirhossein

2017-02-01

Monocyte chemoattractant/chemotactic protein-1 (MCP-1), a member of the CC chemokine family, is one of the key chemokines that regulate migration and tissue infiltration of monocytes/macrophages. Its role in the pathophysiology of several inflammatory diseases has been widely recognized, thus making MCP-1 a possible target for anti-inflammatory treatments. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizomes of Curcuma Longa L. (turmeric). Anti-inflammatory action underlies numerous pharmacological effects of curcumin in the control and prevention of several diseases. The purpose of this review is to evaluate the effects of curcumin on the regulation of MCP-1 as a key mediator of chemotaxis and inflammation, and the biological consequences thereof. In vitro studies have shown that curcumin can decrease MCP-1 production in various cell lines. Animal studies have also revealed that curcumin can attenuate MCP-1 expression and improve a range of inflammatory diseases through multiple molecular targets and mechanisms of action. There is limited data from human clinical trials showing the decreasing effect of curcumin on MCP-1 concentrations and improvement of the course of inflammatory diseases. Most of the in vitro and animal studies confirm that curcumin exert its MCP-1-lowering and anti-inflammatory effects by down-regulating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway. As yet, there is limited data from human clinical trials showing the effect of curcumin on MCP-1 levels and improvement of the course of inflammatory diseases. More evidence, especially from human studies, is needed to better assess the effects of curcumin on circulating MCP-1 in different human diseases and the role of this modulatory effect in the putative anti-inflammatory properties of curcumin. Copyright © 2016 Elsevier Ltd. All rights reserved.

Kynurenines in CNS disease: regulation by inflammatory cytokines

PubMed Central

Campbell, Brian M.; Charych, Erik; Lee, Anna W.; Möller, Thomas

2014-01-01

The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the “neurotoxic” and “neuroprotective” arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders. PMID:24567701

Purinergic signaling modulates the cerebral inflammatory response in experimentally infected fish with Streptococcus agalactiae: an attempt to improve the immune response.

PubMed

Souza, Carine F; Baldissera, Matheus D; Bottari, Nathiele B; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Baldisserotto, Bernardo

2018-06-01

Appropriate control of the immune response is a critical determinant of fish health, and the purinergic cascade has an important role in the immune and inflammatory responses. This cascade regulates the levels of adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate and adenosine (Ado), molecules involved in physiological or pathological events as inflammatory and anti-inflammatory mediators. Thus, the aim of this study was to evaluate whether purinergic signaling, through the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA), is capable of modulating the cerebral immune and inflammatory responses in silver catfish that is experimentally infected with Streptococcus agalactiae. Cerebral NTPDase (with ATP as substrate) and 5'-nucleotidase activities increased, while ADA activity decreased in silver catfish that is experimentally infected with S. agalactiae, compared to the control group. Moreover, the cerebral levels of ATP and Ado increased in infected animals compared to the uninfected control group. Brain histopathology in infected animals revealed inflammatory demyelination (the presence of occasional bubbly collections), increased cellular density in the area near to pia-mater and intercellular edema. Based on this evidence, the modulation of the purinergic cascade by the enzymes NTPDase, 5'-nucleotidase, and ADA exerts an anti-inflammatory profile due to the regulation of ATP and Ado levels. This suggests involvement of purinergic enzymes on streptococcosis pathogenesis, through regulating cerebral ATP and Ado levels, molecules known to participate in physiological or pathological events as inflammatory and anti-inflammatory mediators, respectively. In summary, the modulation of the cerebral purinergic cascade exerts an anti-inflammatory profile in an attempt to reduce inflammatory damage.

Targeting congestion in allergic rhinitis: the importance of intranasal corticosteroids.

PubMed

Marple, Bradley F

2008-01-01

The cardinal nasal symptoms of allergic rhinitis (AR) are sustained by an underlying inflammatory process. Congestion is one of the most prominent and distressing symptoms for patients and is strongly associated with a broadly deteriorated quality of life and significant losses in productivity. The purpose of this study was to explore the role of intranasal corticosteroids (INSs) in down-regulating the inflammatory response to allergen and their clinical efficacy on AR symptoms, particularly congestion. AR is characterized by an influx of inflammatory cells and mediators into the nasal mucosa after antigen exposure. The response is biphasic, encompassing an early and a late phase. Antigen exposure has a priming effect, decreasing the threshold for subsequent allergic reaction on rechallenge and increasing the responsiveness of the nasal mucosa. INSs are a mainstay of therapy for AR and the most effective intervention for nasal congestion and other nasal symptoms, with established superiority to antihistamines, decongestants, and leukotriene antagonists. In addition to symptom relief, INSs suppress numerous stages of the inflammatory cascade, inhibiting the influx of inflammatory cells and mediators. Topical nasal corticosteroids have a low incidence of local adverse effects, negligible systemic absorption, and excellent safety. Congestion is one of the most bothersome symptoms of AR. INS therapy improves AR symptoms, with particular efficacy in relieving congestion, by attenuating nasal hyperresponsiveness. Pretreatment with INSs has been shown to relieve early and late-phase clinical symptoms of AR. Modification of the disease process results in significant relief of symptoms and leads to fewer disease exacerbations.

Multi-target drugs to address multiple checkpoints in complex inflammatory pathologies: evolutionary cues for novel "first-in-class" anti-inflammatory drug candidates: a reviewer's perspective.

PubMed

Mathew, Geetha; Unnikrishnan, M K

2015-10-01

Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.

Involvement of cholinergic and adenosinergic systems on the branchial immune response of experimentally infected silver catfish with Streptococcus agalactiae.

PubMed

Baldissera, M D; Souza, C F; Doleski, P H; Moreira, K L S; da Veiga, M L; da Rocha, M I U M; Santos, R C V; Baldisserotto, B

2018-01-01

It has been recognized that the cholinergic and adenosinergic systems have an essential role in immune and inflammatory responses during bacterial fish pathogens, such as the enzymes acetylcholinesterase (AChE) and adenosine deaminase (ADA), which are responsible for catalysis of the anti-inflammatory molecules acetylcholine (ACh) and adenosine (Ado) respectively. Thus, the aim of this study was to investigate the involvement of the cholinergic and adenosinergic systems on the immune response and inflammatory process in gills of experimentally infected Rhamdia quelen with Streptococcus agalactiae. Acetylcholinesterase activity decreased, while ACh levels increased in gills of infected animals compared to uninfected animals. On the other hand, a significant increase in ADA activity with a concomitant decrease in Ado levels was observed in infected animals compared to uninfected animals. Based on this evidence, we concluded that infection by S. agalactiae in silver catfish alters the cholinergic and adenosinergic systems, suggesting the involvement of AChE and ADA activities on immune and inflammatory responses, regulating the ACh and Ado levels. In summary, the downregulation of AChE activity exerts an anti-inflammatory profile in an attempt to reduce or prevent the tissue damage, while the upregulation of ADA activity exerts a pro-inflammatory profile, contributing to disease pathophysiology. © 2017 John Wiley & Sons Ltd.

In vitro anti-inflammatory and anti-cancer activities of Cuscuta reflexa Roxb.

PubMed

Suresh, V; Sruthi, V; Padmaja, B; Asha, V V

2011-04-12

To determine anti-inflammatory and anti-cancer activities of Cuscuta reflexa in cell lines (in vitro). Anti-inflammatory activity of the water extract was analysed in vitro using lipopolysaccharide (LPS) induced inflammatory reactions in murine macrophage cell line RAW264.7. The expression of COX-2 and TNF-α genes involved in inflammation was analysed by SQ RT-PCR. EMSA was conducted to analyse the influence of the extract on NF-κB signalling. Anti-cancer activity was analysed on Hep3B cells by MTT assay, DAPI staining, annexin V staining and SQ-RT PCR analysis of BAX, Bcl-2, p53 and survivin. The extract down regulated LPS induced over expression of TNF-α and COX-2 in RAW264.7 cells; blocked NF-κB binding to its motifs and induced apoptosis in Hep3B cells as evidenced from MTT, DAPI staining and annexin V staining assays. The extract up regulated pro-apoptotic factors BAX and p53, and down regulated anti-apoptotic factors Bcl-2 and survivin. The study showed that Cuscuta reflexa inhibits LPS induced inflammatory responses in RAW264.7 cells through interplay of TNF-α, COX-2 and NF-κB signalling. It induced apoptosis in Hep3B cells through the up regulation of p53, BAX and down regulation of Bcl-2 and survivin. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease

PubMed Central

Wollny, Tomasz; Wątek, Marzena; Durnaś, Bonita; Niemirowicz, Katarzyna; Piktel, Ewelina; Żendzian-Piotrowska, Małgorzata; Góźdź, Stanisław; Bucki, Robert

2017-01-01

Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system’s immunity. Progressive intestinal tissue destruction observed in chronic inflammation may be associated with an increased risk of colon cancer. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, functions as a cofactor in inflammatory signaling and becomes a target in the treatment of IBD, which might prevent its conversion to cancer. This paper summarizes new findings indicating the impact of (S1P) on IBD development and IBD-associated carcinogenesis. PMID:28362332

In vitro antioxidant and anti-inflammatory activities of Jaceosidin from Artemisia princeps Pampanini cv. Sajabal.

PubMed

Kim, Min-Jung; Han, Jong-Min; Jin, Yue-Yan; Baek, Nam-In; Bang, Myun-Ho; Chung, Hae-Gon; Choi, Myung-Sook; Lee, Kyung-Tae; Sok, Dai-Eun; Jeong, Tae-Sook

2008-04-01

Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu(2+)-mediated LDL oxidation with IC(50) values of 10.2 microM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-kappaB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-kappaB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.

Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion

PubMed Central

Turner, Mark D.; Chaudhry, Anupama; Nedjai, Belinda

2011-01-01

Cytokines are secreted from macrophages and other cells of the immune system in response to pathogens. Additionally, in autoinflammatory diseases cytokine secretion occurs in the absence of pathogenic stimuli. In the case of TRAPS [TNFR (tumour necrosis factor receptor)-associated periodic syndrome], inflammatory episodes result from mutations in the TNFRSF1A gene that encodes TNFR1. This work remains controversial, however, with at least three distinct separate mechanisms of receptor dysfunction having been proposed. Central to these hypotheses are the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) families of transcriptional activators that are able to up-regulate expression of a number of genes, including pro-inflammatory cytokines. The present review examines each proposed mechanism of TNFR1 dysfunction, and addresses how these processes might ultimately impact upon cytokine secretion and disease pathophysiology. PMID:22115362

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

PubMed Central

Cong, Y; Liu, Z

2015-01-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota.

PubMed

Sun, M; He, C; Cong, Y; Liu, Z

2015-09-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3(+) regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

[Comparison of anti-inflammatory activity between crude Atractylodes lancea and their processed products by stir-baking with bran in rat models of gastric ulcer].

PubMed

Yu, Yan; Jia, Tian-Zhu; Cai, Qian

2016-02-01

To compare the anti-inflammatory activity of the crude Atractylodes lancea (AL) and AL processed products by stir-baking with bran in rat models of gastric ulcer, and preliminarily explore the anti-ulcer mechanisms of AL, the model of gastric ulcer was imitated by local acetic acid injection into gastric mucosa in rats by surgery according to the modified Okabe method. All rats were randomly divided into the following 10 groups： sham-operation group, model group, omeprazole group, Sanjiu Weitai granule group, crude AL low dose group, crude AL middle dose group, crude AL high dose group, processed AL low dose group, processed AL middle dose group, and processed AL high dose group. Rats were administered via intragastric (ig) two times each day, for 10 consecutive days. Blood was collected from the abdominal aorta, serum was separated, and the ulcer tissues were taken. The levels of inflammatory factors interleukin 6, 8 (IL-6, 8), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA expressions of TNF-α and IL-8 in gastric tissues were detected by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). The protein expressions of TNF-α and IL-8 in gastric tissues were detected by immunohistochemistry. Compared with sham-operation group, the levels of TNF-α, IL-8, IL-6, PGE2 as well as the mRNA expressions and protein expressions of TNF-α, IL-8 in gastric tissues were significantly higher in model group. The above levels were reduced in different degrees in all treatment groups. Compared with the crude AL, same dose of processed AL was more effective in decreasing the levels of TNF-α, IL-8, IL-6, PGE2 in serum and gastric tissues and down-regulating the mRNA expressions of TNF-α and IL-8 in gastric tissues, with significant difference in middle dose groups and high dose groups. The results showed that AL had potent anti-inflammatory effects in rat models of gastric ulcer induced by acetic acid, and the processed AL had more obvious effect. The anti-ulcer action of AL could be attributed partly to down-regulating the levels of TNF-α, IL-8, IL-6 and PGE2. Copyright© by the Chinese Pharmaceutical Association.

Inhibition of IRF8 Negatively Regulates Macrophage Function and Impairs Cutaneous Wound Healing.

PubMed

Guo, Yuanyuan; Yang, Zhiyin; Wu, Shan; Xu, Peng; Peng, Yinbo; Yao, Min

2017-02-01

The inflammatory response is essential for normal cutaneous wound healing. Macrophages, as critical inflammatory cells, coordinate inflammation and angiogenesis phases during wound healing. It has been reported that the transcription factor interferon regulatory factor 8 (IRF8), a member of the IRF family, plays a critical role in the development and function of macrophages and is associated with inflammation. However, the role of IRF8 in cutaneous wound healing and its underlying mechanism remain elusive. Through immunohistochemical (IHC) staining, we showed that IRF8 is involved in the wound repair process in mice and patients. Furthermore, we ascertain that the repression of IRF8 by small interfering RNA (siRNA) leads to delayed wound healing. To explore the mechanism by which IRF8 impacts wound healing, we observed its effect on macrophage-related mediators by IHC or real-time PCR. The results demonstrated that the inhibition of IRF8 decreases the mRNA expression of inflammatory mediators associated with M1 macrophage (il-1b, il-6, inos, and tnf-a) but no impact on M2 macrophage-related mediators (arg-1, mrc-1, and il-10) and the number of macrophages in the wounds. Furthermore, the inhibition of IRF8 induced apoptosis in the wounds. In summary, this study demonstrates that the down-regulation of IRF8 in the wound leads to impaired wound healing possibly through the regulation of macrophage function and apoptosis in skin wound.

Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes

PubMed Central

Beurel, Eléonore; Jope, Richard S.

2010-01-01

Inflammatory tolerance is the down-regulation of inflammation upon repeated stimuli, which is well-established to occur in peripheral immune cells. However, less is known about inflammatory tolerance in the brain although it may provide an important protective mechanism from detrimental consequences of prolonged inflammation, which appears to occur in many psychiatric and neurodegenerative conditions. Array analysis of 308 inflammatory molecules produced by mouse primary astrocytes after two sequential stimulations with lipopolysaccharide (LPS) distinguished three classes, tolerant, sensitized and unaltered groups. For many of these inflammatory molecules, inhibition of glycogen synthase kinase-3 (GSK3) increased tolerance and reduced sensitization. Focusing on LPS-tolerance in interleukin-6 (IL-6) production, we found that microglia exhibited a strong tolerance response that matched that of macrophages, whereas astrocytes exhibited only partial tolerance. The astrocyte semi-tolerance was found to be regulated by GSK3. GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance. PMID:20553816

Ginsenoside Rg1 exerts synergistic anti-inflammatory effects with low doses of glucocorticoids in vitro.

PubMed

Song, Yanqin; Zhao, Feng; Zhang, Leiming; Du, Yuan; Wang, Tian; Fu, Fenghua

2013-12-01

Glucocorticoids (GCs) are usually used to treat inflammatory diseases. However, they cause severe and irreversible side effects, which limit the use of these compounds. Ginsenoside Rg1 had been demonstrated to possess anti-inflammatory and anti-cancer effects. The present study was designed to investigate whether Rg1 exhibits synergistic anti-inflammatory effects when combined with glucocorticoids. After stimulated by lipopolysaccharide (LPS), murine macrophagic RAW264.7 cells were treated with Rg1, corticosterone (Cort) or Rg1 and Cort. Then nitric oxide (NO), tumor necrosis factor-α (TNF-α) and glucocorticoid receptor (GR) expression were measured. The results showed that Rg1 or Cort could reduce the production of NO and TNF-α, and Rg1 dose-dependently up-regulated GR expression, while Cort dose-dependently down-regulated GR expression. The combination of low concentrations of Rg1 with Cort, which alone could not markedly inhibit the release of inflammatory factors, inhibited the secretion of NO and TNF-α in LPS-stimulated RAW264.7 macrophage cells, and up-regulated the expression of GR. The findings suggested Rg1 can synergize with glucocorticoid to enhance its anti-inflammatory effect. © 2013.

Decursinol angelate blocks transmigration and inflammatory activation of cancer cells through inhibition of PI3K, ERK and NF-kappaB activation.

PubMed

Kim, Won-Jung; Lee, Min-Young; Kim, Jung-Hee; Suk, Kyoungho; Lee, Won-Ha

2010-10-01

Inflammation is known to be closely associated with the development of cancer. Decursinol angelate (DA), a coumarin compound isolated from Angelica gigas and related compounds have been shown to possess potent anti-inflammatory activities. However, little is known about their effects on the inflammatory processes associated with cancer. In this study, the anti-inflammatory effect of DA was evaluated in cancer cell lines with respect to cellular invasion through the extracellular matrix (ECM) and the expression of pro-inflammatory mediators such as cytokine, cell adhesion molecules and matrix metalloproteinase (MMP)-9. DA inhibited the invasion of fibrosarcoma cell line, HT1080 and breast cancer cell line, MDA-MB-231 in the Matrigel invasion assay. DA-mediated suppression of cancer cell invasion was accomplished by suppression of PI3K activity known to be associated with cytoskeletal rearrangement related to cellular migration. DA also suppressed the adhesion of cancer cells to ECM mediated by down-regulation of beta(1)-integrin expression levels. Furthermore, DA inhibited the expression of pro-inflammatory cytokines and MMP-9 through suppression of PI3K, ERK and NF-kappaB activation. These results demonstrate that DA suppresses invasion and inflammatory activation of cancer cells through modulation of PI3K/AKT, ERK and NF-kappaB. These anti-inflammatory activities of DA may contribute to its anti-cancer activity. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1.

PubMed

Yu, Liming; Li, Qing; Yu, Bo; Yang, Yang; Jin, Zhenxiao; Duan, Weixun; Zhao, Guolong; Zhai, Mengen; Liu, Lijun; Yi, Dinghua; Chen, Min; Yu, Shiqiang

2016-01-01

Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate.

PubMed

Brighenti, Elisa; Giannone, Ferdinando Antonino; Fornari, Francesca; Onofrillo, Carmine; Govoni, Marzia; Montanaro, Lorenzo; Treré, Davide; Derenzini, Massimo

2016-09-27

Chronic inflammation is a risk factor for the onset of cancer and the regular use of aspirin reduces the risk of cancer development. Here we showed that therapeutic dosages of aspirin counteract the pro-tumorigenic effects of the inflammatory cytokine interleukin(IL)-6 in cancer and non-cancer cell lines, and in mouse liver in vivo. We found that therapeutic dosages of aspirin prevented IL-6 from inducing the down-regulation of p53 expression and the acquisition of the epithelial mesenchymal transition (EMT) phenotypic changes in the cell lines. This was the result of a reduction in c-Myc mRNA transcription which was responsible for a down-regulation of the ribosomal protein S6 expression which, in turn, slowed down the rRNA maturation process, thus reducing the ribosome biogenesis rate. The perturbation of ribosome biogenesis hindered the Mdm2-mediated proteasomal degradation of p53, throughout the ribosomal protein-Mdm2-p53 pathway. P53 stabilization hindered the IL-6 induction of the EMT changes. The same effects were observed in livers from mice stimulated with IL-6 and treated with aspirin. It is worth noting that aspirin down-regulated ribosome biogenesis, stabilized p53 and up-regulated E-cadherin expression in unstimulated control cells also. In conclusion, these data showed that therapeutic dosages of aspirin increase the p53-mediated tumor-suppressor activity of the cells thus being in this way able to reduce the risk of cancer onset, either or not linked to chronic inflammatory processes.

Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate

PubMed Central

Brighenti, Elisa; Giannone, Ferdinando Antonino; Fornari, Francesca; Onofrillo, Carmine; Govoni, Marzia; Montanaro, Lorenzo; Treré, Davide; Derenzini, Massimo

2016-01-01

Chronic inflammation is a risk factor for the onset of cancer and the regular use of aspirin reduces the risk of cancer development. Here we showed that therapeutic dosages of aspirin counteract the pro-tumorigenic effects of the inflammatory cytokine interleukin(IL)-6 in cancer and non-cancer cell lines, and in mouse liver in vivo. We found that therapeutic dosages of aspirin prevented IL-6 from inducing the down-regulation of p53 expression and the acquisition of the epithelial mesenchymal transition (EMT) phenotypic changes in the cell lines. This was the result of a reduction in c-Myc mRNA transcription which was responsible for a down-regulation of the ribosomal protein S6 expression which, in turn, slowed down the rRNA maturation process, thus reducing the ribosome biogenesis rate. The perturbation of ribosome biogenesis hindered the Mdm2-mediated proteasomal degradation of p53, throughout the ribosomal protein-Mdm2-p53 pathway. P53 stabilization hindered the IL-6 induction of the EMT changes. The same effects were observed in livers from mice stimulated with IL-6 and treated with aspirin. It is worth noting that aspirin down-regulated ribosome biogenesis, stabilized p53 and up-regulated E-cadherin expression in unstimulated control cells also. In conclusion, these data showed that therapeutic dosages of aspirin increase the p53-mediated tumor-suppressor activity of the cells thus being in this way able to reduce the risk of cancer onset, either or not linked to chronic inflammatory processes. PMID:27557515

Proteomic and Metabolomic Analyses Reveal Contrasting Anti-Inflammatory Effects of an Extract of Mucor Racemosus Secondary Metabolites Compared to Dexamethasone.

PubMed

Meier, Samuel M; Muqaku, Besnik; Ullmann, Ronald; Bileck, Andrea; Kreutz, Dominique; Mader, Johanna C; Knasmüller, Siegfried; Gerner, Christopher

2015-01-01

Classical drug assays are often confined to single molecules and targeting single pathways. However, it is also desirable to investigate the effects of complex mixtures on complex systems such as living cells including the natural multitude of signalling pathways. Evidence based on herbal medicine has motivated us to investigate potential beneficial health effects of Mucor racemosus (M rac) extracts. Secondary metabolites of M rac were collected using a good-manufacturing process (GMP) approved production line and a validated manufacturing process, in order to obtain a stable product termed SyCircue (National Drug Code USA: 10424-102). Toxicological studies confirmed that this product does not contain mycotoxins and is non-genotoxic. Potential effects on inflammatory processes were investigated by treating stimulated cells with M rac extracts and the effects were compared to the standard anti-inflammatory drug dexamethasone on the levels of the proteome and metabolome. Using 2D-PAGE, slight anti-inflammatory effects were observed in primary white blood mononuclear cells, which were more pronounced in primary human umbilical vein endothelial cells (HUVECs). Proteome profiling based on nLC-MS/MS analysis of tryptic digests revealed inhibitory effects of M rac extracts on pro-inflammatory cytoplasmic mediators and secreted cytokines and chemokines in these endothelial cells. This finding was confirmed using targeted proteomics, here treatment of stimulated cells with M rac extracts down-regulated the secretion of IL-6, IL-8, CXCL5 and GROA significantly. Finally, the modulating effects of M rac on HUVECs were also confirmed on the level of the metabolome. Several metabolites displayed significant concentration changes upon treatment of inflammatory activated HUVECs with the M rac extract, including spermine and lysophosphatidylcholine acyl C18:0 and sphingomyelin C26:1, while the bulk of measured metabolites remained unaffected. Interestingly, the effects of M rac treatment on lipids were orthogonal to the effect of dexamethasone underlining differences in the overall mode of action.

Anti-aging effects of guanosine in glial cells.

PubMed

Souza, Débora Guerini; Bellaver, Bruna; Bobermin, Larissa Daniele; Souza, Diogo Onofre; Quincozes-Santos, André

2016-12-01

Guanosine, a guanine-based purine, has been shown to exert beneficial roles in in vitro and in vivo injury models of neural cells. Guanosine is released from astrocytes and modulates important astroglial functions, including glutamatergic metabolism, antioxidant, and anti-inflammatory activities. Astrocytes are crucial for regulating the neurotransmitter system and synaptic information processes, ionic homeostasis, energy metabolism, antioxidant defenses, and the inflammatory response. Aging is a natural process that induces numerous changes in the astrocyte functionality. Thus, the search for molecules able to reduce the glial dysfunction associated with aging may represent an approach for avoiding the onset of age-related neurological diseases. Hence, the aim of this study was to evaluate the anti-aging effects of guanosine, using primary astrocyte cultures from newborn, adult, and aged Wistar rats. Concomitantly, we evaluated the role of heme oxygenase 1 (HO-1) in guanosine-mediated glioprotection. We observed age-dependent changes in glutamate uptake, glutamine synthetase (GS) activity, the glutathione (GSH) system, pro-inflammatory cytokine (tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)) release, and the transcriptional activity of nuclear factor kB (NFkB), which were prevented by guanosine in an HO-1-dependent manner. Our findings suggest guanosine to be a promising therapeutic agent able to provide glioprotection during the aging process. Thus, this study contributes to the understanding of the cellular and molecular mechanisms of guanosine in the aging process.

Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

PubMed Central

Bornemann, Klaus D.; Wiederhold, Karl-Heinz; Pauli, Chantal; Ermini, Florian; Stalder, Martina; Schnell, Lisa; Sommer, Bernd; Jucker, Mathias; Staufenbiel, Matthias

2001-01-01

A microglial response is part of the inflammatory processes in Alzheimer’s disease (AD). We have used APP23 transgenic mice overexpressing human amyloid precursor protein with the Swedish mutation to characterize this microglia response to amyloid deposits in aged mice. Analyses with MAC-1 and F4/80 antibodies as well as in vivo labeling with bromodeoxyuridine demonstrate that microglia in the plaque vicinity are in an activated state and that proliferation contributes to their accumulation at the plaque periphery. The amyloid-induced microglia activation may be mediated by scavenger receptor A, which is generally elevated, whereas the increased immunostaining of the receptor for advanced glycation end products is more restricted. Although components of the phagocytic machinery such as macrosialin and Fc receptors are increased in activated microglia, efficient clearance of amyloid is missing seemingly because of the lack of amyloid-bound autoantibodies. Similarly, although up-regulation of major histocompatibility complex class II (IA) points toward an intact antigen-presenting function of microglia, lack of T and B lymphocytes does not indicate a cell-mediated immune response in the brains of APP23 mice. The similar characteristics of microglia in the APP23 mice and in AD render the mouse model suitable to study the role of inflammatory processes during AD pathogenesis. PMID:11141480

Long non-coding RNA HOTAIR promotes UVB-induced apoptosis and inflammatory injury by up-regulation of PKR in keratinocytes.

PubMed

Liu, Guo; Zhang, Wenhao

2018-06-11

Excessive exposure to ultraviolet (UV) rays can cause damage of the skin and may induce cancer, immunosuppression, photoaging, and inflammation. The long non-coding RNA (lncRNA) HOX antisense intergenic RNA (HOTAIR) is involved in multiple human biological processes. However, its role in UVB-induced keratinocyte injury is unclear. This study was performed to investigate the effects of HOTAIR in UVB-induced apoptosis and inflammatory injury in human keratinocytes (HaCaT cells). Quantitative real-time polymerase chain reaction was performed to analyze the expression levels of HOTAIR, PKR, TNF-α, and IL-6. Cell viability was measured using trypan blue exclusion method and cell apoptosis using flow cytometry and western blot. ELISA was used to measure the concentrations of TNF-α and IL-6. Western blot was used to measure the expression of PKR, apoptosis-related proteins, and PI3K/AKT and NF-κB pathway proteins. UVB induced HaCaT cell injury by inhibiting cell viability and promoting cell apoptosis and expressions of IL-6 and TNF-α. UVB also promoted the expression of HOTAIR. HOTAIR suppression increased cell viability and decreased apoptosis and expression of inflammatory factors in UVB-treated cells. HOTAIR also promoted the expression of PKR. Overexpression of HOTAIR decreased cell viability and increased cell apoptosis and expression of inflammatory factors in UVB-treated cells by upregulating PKR. Overexpression of PKR decreased cell viability and promoted cell apoptosis in UVB-treated cells. Overexpression of PKR activated PI3K/AKT and NF-κB pathways. Our findings identified an essential role of HOTAIR in promoting UVB-induced apoptosis and inflammatory injury by up-regulating PKR in keratinocytes.

Post-Translational Modification Control of Innate Immunity.

PubMed

Liu, Juan; Qian, Cheng; Cao, Xuetao

2016-07-19

A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Guinea-pig interpubic joint (symphysis pubica) relaxation at parturition: Underlying cellular processes that resemble an inflammatory response

PubMed Central

Rodríguez, Horacio A; Ortega, Hugo H; Ramos, Jorge G; Muñoz-de-Toro, Mónica; Luque, Enrique H

2003-01-01

Background At term, cervical ripening in coordination with uterine contractions becomes a prerequisite for a normal vaginal delivery. Currently, cervical ripening is considered to occur independently from uterine contractions. Many evidences suggest that cervical ripening resembles an inflammatory process. Comparatively little attention has been paid to the increased flexibility of the pelvic symphysis that occurs in many species to enable safe delivery. The aim of this study was to investigate whether the guinea-pig interpubic joint relaxation process observed during late pregnancy and parturition resembles an inflammatory process. Methods Samples of pubic symphysis were taken from pregnant guinea-pigs sacrificed along gestation, parturition and postpartum. Serial sections of paraffin-embedded tissues were used to measure the interpubic distance on digitalized images, stained with Giemsa to quantify leukocyte infiltration and to describe the vascular area changes, or studied by the picrosirius-polarization method to evaluate collagen remodeling. P4 and E2 serum levels were measured by a sequential immunometric assay. Results Data showed that the pubic relaxation is associated with an increase in collagen remodeling. In addition, a positive correlation between E2 serum levels and the increase in the interpubic distance was found. On the other hand, a leukocyte infiltration in the interpubic tissue around parturition was described, with the presence of almost all inflammatory cells types. At the same time, histological images show an increase in vascular area (angiogenesis). Eosinophils reached their highest level immediately before parturition; whereas for the neutrophilic and mononuclear infiltration higher values were recorded one day after parturition. Correlation analysis showed that eosinophils and mononuclear cells were positively correlated with E2 levels, but only eosinophilic infiltration was associated with collagen remodeling. Additionally, we observed typical histological images of dissolution of the connective tissue matrix around eosinophils. Conclusion The present study shows that a timely regulated influx of infiltrating leukocytes is associated with an extensive collagen remodeling process that allows the pubic separation for a normal delivery in guinea-pig. Thus, the findings in this study support the hypothesis that the guinea-pig pubic symphyseal relaxation at parturition resembles an inflammatory process. PMID:14633278

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

PubMed

Cherry, Anne D; Piantadosi, Claude A

2015-04-20

Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Hantaviruses induce cell type- and viral species-specific host microRNA expression signatures

PubMed Central

Shin, Ok Sarah; Kumar, Mukesh; Yanagihara, Richard; Song, Jin-Won

2014-01-01

The mechanisms of hantavirus-induced modulation of host cellular immunity remain poorly understood. Recently, microRNAs (miRNAs) have emerged as a class of essential regulators of host immune response genes. To ascertain if differential host miRNA expression toward representative hantavirus species correlated with immune response genes, miRNA expression profiles were analyzed in human endothelial cells, macrophages and epithelial cells infected with pathogenic and nonpathogenic rodent- and shrew-borne hantaviruses. Distinct miRNA expression profiles were observed in a cell type- and viral species-specific pattern. A subset of miRNAs, including miR-151-5p and miR-1973, were differentially expressed between Hantaan virus and Prospect Hill virus. Pathway analyses confirmed that the targets of selected miRNAs were associated with inflammatory responses and innate immune receptor-mediated signaling pathways. Our data suggest that differential immune responses following hantavirus infection may be regulated in part by cellular miRNA through dysregulation of genes critical to the inflammatory process. PMID:24074584

Resolution of inflammation pathways in preeclampsia-a narrative review.

PubMed

Perucci, Luiza Oliveira; Corrêa, Mário Dias; Dusse, Luci Maria; Gomes, Karina Braga; Sousa, Lirlândia Pires

2017-08-01

Preeclampsia (PE) is one of the leading causes of maternal morbidity and mortality worldwide. This disease is believed to occur in two stages with placental dysfunction in early pregnancy leading to maternal clinical findings after 20 weeks of gestation, as consequence of systemic inflammation, oxidative stress, and endothelial dysfunction. Much evidence suggests that PE women display an overshooting inflammatory response throughout pregnancy due to an unbalanced regulation of innate and adaptive immune responses. Recently, it has been suggested that dysregulation of endogenous protective pathways might be associated with PE etiopathogenesis. Resolution of inflammation is an active process coordinated by mediators from diverse nature that regulate key cellular events to restore tissue homeostasis. Inadequate or insufficient resolution of inflammation is believed to play an important role in the development of chronic inflammatory diseases, like PE. In this narrative review, we discuss possible pro-resolution pathways that might be compromised in PE women, which could be targets to novel therapeutic strategies in this disease.

Modulating inflammation through the negative regulation of NF-κB signaling.

PubMed

Rothschild, Daniel E; McDaniel, Dylan K; Ringel-Scaia, Veronica M; Allen, Irving C

2018-02-01

Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto-inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies. ©2018 Society for Leukocyte Biology.

Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide-stimulated inflammatory responses in RAW 264.7 macrophages

PubMed Central

Ko, Wan-Kyu; Lee, Soo-Hong; Kim, Sung Jun; Jo, Min-Jae; Kumar, Hemant; Han, In-Bo; Sohn, Seil

2017-01-01

Purpose The aim of this study was to investigate the anti-inflammatory effects of Ursodeoxycholic acid (UDCA) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Methods We induced an inflammatory process in RAW 264.7 macrophages using LPS. The anti-inflammatory effects of UDCA on LPS-stimulated RAW 264.7 macrophages were analyzed using nitric oxide (NO). Pro-inflammatory and anti-inflammatory cytokines were analyzed by quantitative real time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 in mitogen-activated protein kinase (MAPK) signaling pathways and nuclear factor kappa-light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) signaling pathways were evaluated by western blot assays. Results UDCA decreased the LPS-stimulated release of the inflammatory mediator NO. UDCA also decreased the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1-α (IL-1α), interleukin 1-β (IL-1β), and interleukin 6 (IL-6) in mRNA and protein levels. In addition, UDCA increased an anti-inflammatory cytokine interleukin 10 (IL-10) in the LPS-stimulated RAW 264.7 macrophages. UDCA inhibited the expression of inflammatory transcription factor nuclear factor kappa B (NF-κB) in LPS-stimulated RAW 264.7 macrophages. Furthermore, UDCA suppressed the phosphorylation of ERK, JNK, and p38 signals related to inflammatory pathways. In addition, the phosphorylation of IκBα, the inhibitor of NF-κB, also inhibited by UDCA. Conclusion UDCA inhibits the pro-inflammatory responses by LPS in RAW 264.7 macrophages. UDCA also suppresses the phosphorylation by LPS on ERK, JNK, and p38 in MAPKs and NF-κB pathway. These results suggest that UDCA can serve as a useful anti-inflammatory drug. PMID:28665991

The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisele, Petra Sabine; Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich; Furrer, Regula

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed amore » PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12). In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation. - Highlights: • Muscle PGC-1s are insufficient to prevent acute systemic inflammation. • The muscle PGC-1s however promote a local anti-inflammatory environment. • This anti-inflammatory environment could contribute to the therapeutic effect of the PGC-1s.« less

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease.

PubMed

Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

2016-01-21

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

IL-35, a hallmark of immune-regulation in cancer progression, chronic infections and inflammatory diseases.

PubMed

Teymouri, Manouchehr; Pirro, Matteo; Fallarino, Francesca; Gargaro, Marco; Sahebkar, Amirhosein

2018-03-25

Cytokine members of the IL-12 family have attracted enormous attention in the last few years, with IL-35 being the one of the most attractive-suppressive cytokine. IL-35 is an important mediator of regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal-maternal tolerance, maintenance of self-tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune-homoeostasis on the aforementioned issues, taking IL-35 as the hallmark of regulatory responses. The dilemma between immune-mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL-35 requires additional immune-regulatory cytokines, such as IL-10 and TGF-β, to induce effective and maximal anti-inflammatory effects suggest that immune-regulation requires multi-factorial analysis of many immune playmakers rather than a specific immune target. © 2018 UICC.

Role of Th17 Cells in the Pathogenesis of Human IBD

PubMed Central

Gálvez, Julio

2014-01-01

The gastrointestinal tract plays a central role in immune system, being able to mount efficient immune responses against pathogens, keeping the homeostasis of the human gut. However, conditions like Crohn's disease (CD) or ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD), are related to an excessive and uncontrolled immune response against normal microbiota, through the activation of CD4+ T helper (Th) cells. Classically, IBD was thought to be primarily mediated by Th1 cells in CD or Th2 cells in UC, but it is now known that Th17 cells and their related cytokines are crucial mediators in both conditions. Th17 cells massively infiltrate the inflamed intestine of IBD patients, where they produce interleukin- (IL-) 17A and other cytokines, triggering and amplifying the inflammatory process. However, these cells show functional plasticity, and they can be converted into either IFN-γ producing Th1 cells or regulatory T cells. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut. Deeper insights into their plasticity in inflammatory conditions will contribute to advancing our understanding of the mechanisms that regulate mucosal homeostasis and inflammation in the gut, promoting the design of novel therapeutic approaches for IBD. PMID:25101191

Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside-a Comprehensive Review.

PubMed

Alves, C Henrique; Farrell, Eric; Vis, Marijn; Colin, Edgar M; Lubberts, Erik

2016-08-01

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions.

Inflammation and oxidative stress in vertebrate host–parasite systems

PubMed Central

Sorci, Gabriele; Faivre, Bruno

2008-01-01

Innate, inflammation-based immunity is the first line of vertebrate defence against micro-organisms. Inflammation relies on a number of cellular and molecular effectors that can strike invading pathogens very shortly after the encounter between inflammatory cells and the intruder, but in a non-specific way. Owing to this non-specific response, inflammation can generate substantial costs for the host if the inflammatory response, and the associated oxygen-based damage, get out of control. This imposes strong selection pressure that acts to optimize two key features of the inflammatory response: the timing of activation and resolution (the process of downregulation of the response). In this paper, we review the benefits and costs of inflammation-driven immunity. Our aim is to emphasize the importance of resolution of inflammation as a way of maintaining homeostasis against oxidative stress and to prevent the ‘horror autotoxicus’ of chronic inflammation. Nevertheless, host immune regulation also opens the way to pathogens to subvert host defences. Therefore, quantifying inflammatory costs requires assessing (i) short-term negative effects, (ii) delayed inflammation-driven diseases, and (iii) parasitic strategies to subvert inflammation. PMID:18930878

Anti-inflammatory effect of miltirone on inflammatory bowel disease via TLR4/NF-κB/IQGAP2 signaling pathway.

PubMed

Wang, Hongjian; Gu, Junfei; Hou, Xuefeng; Chen, Juan; Yang, Nan; Liu, Ying; Wang, Gang; Du, Mei; Qiu, Huihui; Luo, Yi; Jiang, Ziyu; Feng, Liang

2017-01-01

Inflammatory bowel disease (IBD) is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. This study was conducted to evaluate the anti-inflammation effect of miltirone against IBD in vitro and in vivo, and try to explore the underlying mechanisms. Miltirone could extenuate the loss of colon length and weight caused by TNBS. Additionally, macroscopic scores and DAI were reduced significantly compared with the TNBS group. The levels of TNF-α, IL-1β, IL-6 and IL-8 were increased significantly with the induction by TNBS (100mg/kg) or LPS (0.5mg/mL). Interestingly, miltirone could down-regulate the levels of these increased pro-inflammatory factors in a dose-dependent manner both in vivo and in vitro. The protein and mRNA expressions of TLR4, MyD88, NF-κB p65 were up-regulated by TNBS or LPS stimulation. CRX-526, the TLR4 inhibitor, as well as miltirone could significantly suppress the increased protein and mRNA expressions. Miltirone could up-regulate the descreased IQGAP2 expression induced by LPS. All these revealed that the anti-inflammatory effect of miltirone on IBD may be via regulating TLR4/NF-κB/IQGAP2 signaling pathway. The findings might supply beneficial hints for the drug research to cure the IBD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Roles of neutrophils in the regulation of the extent of human inflammation through delivery of IL-1 and clearance of chemokines

PubMed Central

Basran, Alexander; Jabeen, Maisha; Bingle, Lynne; Stokes, Clare A.; Dockrell, David H.; Whyte, Moira K. B.; Walmsley, Sarah R.; Higgins, Kathryn R.; Vogel, Stefanie N.; Wilson, Heather L.; Prince, Lynne R.; Prestwich, Elizabeth C.; Sabroe, Ruth A.; Parker, Lisa C.; Sabroe, Ian

2013-01-01

This study examined the establishment of neutrophilic inflammation in humans. We tested the hypotheses that neutrophil recruitment was associated with local CXCL8 production and that neutrophils themselves might contribute to the regulation of the size of the inflammatory response. Humans were challenged i.d. with endotoxin. Biopsies of these sites were examined for cytokine production and leukocyte recruitment by qPCR and IHC. Additional in vitro models of inflammation examined the ability of neutrophils to produce and sequester cytokines relevant to neutrophilic inflammation. i.d. challenge with 15 ng of a TLR4-selective endotoxin caused a local inflammatory response, in which 1% of the total biopsy area stained positive for neutrophils at 6 h, correlating with 100-fold up-regulation in local CXCL8 mRNA generation. Neutrophils themselves were the major source of the early cytokine IL-1β. In vitro, neutrophils mediated CXCL8 but not IL-1β clearance (>90% clearance of ≤2 nM CXCL8 over 24 h). CXCL8 clearance was at least partially receptor-dependent and modified by inflammatory context, preserved in models of viral infection but reduced in models of bacterial infection. In conclusion, in a human inflammatory model, neutrophils are rapidly recruited and may regulate the size and outcome of the inflammatory response through the uptake and release of cytokines and chemokines in patterns dependent on the underlying inflammatory stimulus. PMID:22904343

The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder

PubMed Central

Zhu, Conghui; Xie, Qunhui; Zhao, Bin

2014-01-01

AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Since the AhR signaling pathway represents an important link between environmental stimulators and immune-mediated inflammatory disorder, it has become the object of great interest among researchers recently. The current review discusses new insights into the mechanisms of action of a select group of inflammatory autoimmune diseases and the ligand-activated AhR signaling pathway. Representative ligands of AhR, both exogenous and endogenous, are also reviewed relative to their potential use as tools for understanding the role of AhR and as potential therapeutics for the treatment of various inflammatory autoimmune diseases, with a focus on CD4 helper T cells, which play important roles both in self-immune tolerance and in inflammatory autoimmune diseases. Evidence indicating the potential use of these ligands in regulating inflammation in various diseases is highlighted, and potential mechanisms of action causing immune system effects mediated by AhR signaling are also discussed. The current review will contribute to a better understanding of the role of AhR and its signaling pathway in CD4 helper T cell mediated inflammatory disorder. Considering the established importance of AhR in immune regulation and its potential as a therapeutic target, we also think that both further investigation into the molecular mechanisms of immune regulation that are mediated by the ligand-specific AhR signaling pathway, and integrated research and development of new therapeutic drug candidates targeting the AhR signaling pathway should be pursued urgently. PMID:24905409

Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

PubMed

Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D; Giguère, Vincent; Jo, Eun-Kyeong

2015-07-21

The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. Copyright © 2015 Elsevier Inc. All rights reserved.

Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marín-Prida, Javier; Pavón-Fuentes, Nancy; Llópiz-Arzuaga, Alexey

2013-10-01

Since the inflammatory response and oxidative stress are involved in the stroke cascade, we evaluated here the effects of Phycocyanobilin (PCB, the C-Phycocyanin linked tetrapyrrole) on PC12 cell survival, the gene expression and the oxidative status of hypoperfused rat brain. After the permanent bilateral common carotid arteries occlusion (BCCAo), the animals were treated with saline or PCB, taking samples 24 h post-surgery. Global gene expression was analyzed with GeneChip Rat Gene ST 1.1 from Affymetrix; the expression of particular genes was assessed by the Fast SYBR Green RT-PCR Master Mix and Bioplex methods; and redox markers (MDA, PP, CAT, SOD)more » were evaluated spectrophotometrically. The PCB treatment prevented the H{sub 2}O{sub 2} and glutamate induced PC12 cell injury assessed by the MTT assay, and modulated 190 genes (93 up- and 97 down-regulated) associated to several immunological and inflammatory processes in BCCAo rats. Furthermore, PCB positively modulated 19 genes mostly related to a detrimental pro-inflammatory environment and counteracted the oxidative imbalance in the treated BCCAo animals. Our results support the view of an effective influence of PCB on major inflammatory mediators in acute cerebral hypoperfusion. These results suggest that PCB has a potential to be a treatment for ischemic stroke for which further studies are needed. - Highlights: • Phycocyanobilin (PCB) prevents H{sub 2}O{sub 2} and glutamate induced PC12 cell viability loss. • Anterior cortex and striatum are highly vulnerable to cerebral hypoperfusion (CH). • PCB modulates 190 genes associated to inflammation in acute CH. • PCB regulates 19 genes mostly related to a detrimental pro-inflammatory environment. • PCB restores redox and immune balances showing promise as potential stroke therapy.« less

An IκB Kinase-regulated feed-forward circuit prolongs inflammation

PubMed Central

Perez, Jessica M.; Chirieleison, Steven M.; Abbott, Derek W.

2015-01-01

Summary Loss of NF-κB signaling causes immunodeficiency while inhibition of NF-κB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-κB signaling must therefore be tightly regulated, and while many mechanisms to downregulate NF-κB have been elucidated, there have only been limited studies demonstrating positive feed-forward regulation of NF-κB signaling. In this work, we use a bioinformatic and proteomic approach to discover that the IKK family of proteins can phosphorylate the E3 ubiquitin ligase, ITCH, a critical downregulator of TNF-mediated NF-κB activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-κB signaling and pro-inflammatory cytokine release. Since genetic loss of ITCH mirrors IKK-induced ITCH phosphorylation, we further show that the ITCH−/− mouse’s spontaneous lung inflammation and subsequent death can be delayed when TNF signaling is genetically deleted. This work thus identifies a new positive feed-forward regulation of NF-kB activation that drives inflammatory disease. PMID:26190110

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats.

PubMed

Fang, Jian-Qiao; Du, Jun-Ying; Liang, Yi; Fang, Jun-Fan

2013-03-22

Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat's paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

PubMed Central

2013-01-01

Background Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. Results EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. Conclusions The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats. PMID:23517865

Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

PubMed Central

Corbi, Graziamaria; Bianco, Andrea; Turchiarelli, Viviana; Cellurale, Michele; Fatica, Federica; Daniele, Aurora; Mazzarella, Gennaro; Ferrara, Nicola

2013-01-01

The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD+-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems. PMID:23774840

Substance P up-regulates matrix metalloproteinase-1 and down-regulates collagen in human lung fibroblast.

PubMed

Ramos, Carlos; Montaño, Martha; Cisneros, Jose; Sommer, Bettina; Delgado, Javier; Gonzalez-Avila, Georgina

2007-01-01

Substance P is involved in inflammatory processes, but its effect on extracellular matrix metabolism has not been studied; therefore, the authors evaluated its effect on collagen synthesis and degradation, expression of pro-alpha1(I) collagen, matrix metalloproteinase-1 and -2, and tissue inhibitor of metalloproteinase-1 and -2 in normal human lung fibroblast strains. Substance P induced a decrease in collagen biosynthesis, concomitant to a down-regulation of pro-alpha1(I) collagen mRNA. In contrast, an increase in collagen degradation was observed, accompanied with an up-regulation of matrix metalloproteinase-1. Substance P did not influence tissue inhibitor of metalloproteinase-1 and -2 or matrix metalloproteinase-2 expression. The results suggest that substance P participates in extracellular matrix metabolism.

miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer.

PubMed

Wang, Zhigang; Xu, Lu; Hu, Yinying; Huang, Yanqin; Zhang, Yujuan; Zheng, Xiufen; Wang, Shanshan; Wang, Yifan; Yu, Yanrong; Zhang, Meng; Yuan, Keng; Min, Weiping

2016-05-09

Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.

Endothelial Response to Glucocorticoids in Inflammatory Diseases

PubMed Central

Zielińska, Karolina A.; Van Moortel, Laura; Opdenakker, Ghislain; De Bosscher, Karolien; Van den Steen, Philippe E.

2016-01-01

The endothelium plays a crucial role in inflammation. A balanced control of inflammation requires the action of glucocorticoids (GCs), steroidal hormones with potent cell-specific anti-inflammatory properties. Besides the classic anti-inflammatory effects of GCs on leukocytes, recent studies confirm that endothelial cells also represent an important target for GCs. GCs regulate different aspects of endothelial physiology including expression of adhesion molecules, production of pro-inflammatory cytokines and chemokines, and maintenance of endothelial barrier integrity. However, the regulation of endothelial GC sensitivity remains incompletely understood. In this review, we specifically examine the endothelial response to GCs in various inflammatory diseases ranging from multiple sclerosis, stroke, sepsis, and vasculitis to atherosclerosis. Shedding more light on the cross talk between GCs and endothelium will help to improve existing therapeutic strategies and develop new therapies better tailored to the needs of patients. PMID:28018358

Protective effect of Schizandrin B against damage of UVB irradiated skin cells depend on inhibition of inflammatory pathways.

PubMed

Gao, Chenguang; Chen, Hong; Niu, Cong; Hu, Jie; Cao, Bo

2017-01-02

Schizandrin B is extracted from Schisandra chinensis (Turcz.) Baill. This study evaluated the photoprotective effect of Schizandrin B on oxidative stress injury of the skin caused by UVB-irradiation and the molecular mechanism of the photoprotective effect of Schizandrin B, and we firstly found that Schizandrin B could block Cox-2, IL-6 and IL-18 signal pathway to protect damage of skin cells given by UVB-irradiation. In the research, we found that Schizandrin B can attenuate the UVB-induced toxicity on keratinocytes and dermal fibroblasts in human body, and can outstandingly eliminated intracellular ROS produced by UVB-irradiation. These results demonstrate that Schizandrin B can regulate the function of decreasing intracellular SOD's activity and increasing the expression level of MDA in HaCaT cells result from the guidance of UVB, and it markedly reduced the production of inflammatory factors such as Cox-2, IL-6 or IL-18, decreased the expression level of MMP-1, and interdicted degradation process of collagens in UVB-radiated cells. Therefore, skin keratinocytes can be effectively protected from UVB-radiated damage by Schizandrin B, and UVB-irradiation caused inflammatory responses can be inhibited by attenuating process of ROS generating.

EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT

PubMed Central

Xiaokaiti, Yilixiati; Wu, Haoming; Chen, Ya; Yang, Haopeng; Duan, Jianhui; Li, Xin; Pan, Yan; Tie, Lu; Zhang, Liangren; Li, Xuejun

2015-01-01

Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway. PMID:26177797

Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis

PubMed Central

2013-01-01

Background Tachykinins can have pro-inflammatory as well as healing effects during tissue reorganization and inflammation. Recent studies report an up-regulation in the expression of the substance P (SP)-preferred receptor, the neurokinin-1 receptor, in marked muscle inflammation (myositis). There is, however, only very little information on the expression patterns and levels of tachykinins in this situation. Methods The tachykinin system was analyzed using a rabbit experimental model of muscle overuse, whereby unilateral muscle exercise in combination with electrical stimulation led to muscle derangement and myositis in the triceps surae muscle (experimental length 1–6 weeks). Evaluations were made for both parts of the muscle (soleus and gastrocnemius muscles) in experimental and non-experimental (contralateral) sides. Morphologic evaluation, immunohistochemistry, in situ hybridization and enzyme immunoassay (EIA) analyses were applied. Results Myositis and muscle derangement occurred focally not only in the experimental side but also in the non-experimental side. In the inflammatory areas (focal myositis areas), there were frequent nerve fibers showing tachykinin-like immunoreactivity and which were parts of nerve fascicles and which were freely dispersed in the tissue. Cells in the inflammatory infiltrates showed tachykinin-like immunoreactivity and tachykinin mRNA expression. Specific immunoreactivity and mRNA expression were noted in blood vessel walls of both sides, especially in focally affected areas. With increasing experimental length, we observed an increase in the degree of immunoreactivity in the vessel walls. The EIA analyses showed that the concentration of tachykinin in the tissue on both sides increased in a time-dependent manner. There was a statistical correlation in the concentration of tachykinin and the level of tachykinin immunoreactivity in the blood vessel walls between experimental and non-experimental sides. Conclusions The observations show an up-regulation of the tachykinin system bilaterally during muscle derangement/myositis in response to pronounced unilateral muscle overuse. This up-regulation occurred in inflammatory areas and was related not only to increased tachykinin innervation but also to tachykinin expression in blood vessel walls and inflammatory cells. Importantly, the tachykinin system appears to be an important factor not only ipsilaterally but also contralaterally in these processes. PMID:23587295

Bilateral increase in expression and concentration of tachykinin in a unilateral rabbit muscle overuse model that leads to myositis.

PubMed

Song, Yafeng; Stål, Per S; Yu, Ji-Guo; Forsgren, Sture

2013-04-12

Tachykinins can have pro-inflammatory as well as healing effects during tissue reorganization and inflammation. Recent studies report an up-regulation in the expression of the substance P (SP)-preferred receptor, the neurokinin-1 receptor, in marked muscle inflammation (myositis). There is, however, only very little information on the expression patterns and levels of tachykinins in this situation. The tachykinin system was analyzed using a rabbit experimental model of muscle overuse, whereby unilateral muscle exercise in combination with electrical stimulation led to muscle derangement and myositis in the triceps surae muscle (experimental length 1-6 weeks). Evaluations were made for both parts of the muscle (soleus and gastrocnemius muscles) in experimental and non-experimental (contralateral) sides. Morphologic evaluation, immunohistochemistry, in situ hybridization and enzyme immunoassay (EIA) analyses were applied. Myositis and muscle derangement occurred focally not only in the experimental side but also in the non-experimental side. In the inflammatory areas (focal myositis areas), there were frequent nerve fibers showing tachykinin-like immunoreactivity and which were parts of nerve fascicles and which were freely dispersed in the tissue. Cells in the inflammatory infiltrates showed tachykinin-like immunoreactivity and tachykinin mRNA expression. Specific immunoreactivity and mRNA expression were noted in blood vessel walls of both sides, especially in focally affected areas. With increasing experimental length, we observed an increase in the degree of immunoreactivity in the vessel walls. The EIA analyses showed that the concentration of tachykinin in the tissue on both sides increased in a time-dependent manner. There was a statistical correlation in the concentration of tachykinin and the level of tachykinin immunoreactivity in the blood vessel walls between experimental and non-experimental sides. The observations show an up-regulation of the tachykinin system bilaterally during muscle derangement/myositis in response to pronounced unilateral muscle overuse. This up-regulation occurred in inflammatory areas and was related not only to increased tachykinin innervation but also to tachykinin expression in blood vessel walls and inflammatory cells. Importantly, the tachykinin system appears to be an important factor not only ipsilaterally but also contralaterally in these processes.

Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation

PubMed Central

Leus, Niek G.J.; Zwinderman, Martijn R.H.; Dekker, Frank J.

2016-01-01

Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications are lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed. PMID:27371876

Inflammation and epigenetic regulation in osteoarthritis

PubMed Central

Shen, Jie; Abu-Amer, Yousef; O'Keefe, Regis J.; McAlinden, Audrey

2017-01-01

Osteoarthritis (OA) was once defined as a non-inflammatory arthropathy, but it is now well-recognized that there is a major inflammatory component to this disease. In addition to synovial cells, articular chondrocytes and other cells of diarthrodial joints are also known to express inflammatory mediators. It has been proposed that targeting inflammation pathways could be a promising strategy to treat OA. There have been many reports of cross-talk between inflammation and epigenetic factors in cartilage. Specifically, inflammatory mediators have been shown to regulate levels of enzymes that catalyze changes in DNA methylation and histone structure, as well as alter levels of non-coding RNAs. In addition, expression levels of a number of these epigenetic factors have been shown to be altered in OA, thereby suggesting potential interplay between inflammation and epigenetics in this disease. This review provides information on inflammatory pathways in arthritis and summarizes published research on how epigenetic regulators are affected by inflammation in chondrocytes. Furthermore, we discuss data showing how altered expression of some of these epigenetic factors can induce either catabolic or anti-catabolic effects in response to inflammatory signals. A better understanding of how inflammation affects epigenetic factors in OA may provide us with novel therapeutic strategies to treat this condition. PMID:27389927

The suppressive effect of puerarin on atopic dermatitis-like skin lesions through regulation of inflammatory mediators in vitro and in vivo.

PubMed

Lee, Ji-Hyun; Jeon, Yong-Deok; Lee, Young-Mi; Kim, Dae-Ki

2018-04-15

Atopic dermatitis (AD) is one of the common inflammatory immune disorders. Puerarin is the main isoflavonoid obtained from the root of Pueraria lobata and has been known have ameliorative effects on diverse inflammatory diseases. However, the effects of puerarin on AD have not been uncovered. 2,4-dinitrochlorobenzene (DNCB) was used to induce atopic dermatitis(AD)-like skin lesions on BALB/c mice for 17 days. Further, the BALB/c mice were orally administered puerarin. Puerarin ameliorated DNCB-induced AD-like symptoms in the mice by regulating skin thickness, degranulation of mast cells, and serum immunoglobulin E (IgE). Human keratinocytes (HaCaT cells) were also used to clarify the effects of puerarin on the secretion of pro-inflammatory cytokines. Puerarin inhibited the secretion of inflammatory cytokines and chemokines. The aim of this study was to investigate the protective and alleviative effect of puerarin on AD in vitro and in vivo. The results in this study indicated that puerarin ameliorates AD-like skin lesion and skin inflammation via regulation of various atopic and inflammatory mediators. Therefore, puerarin might be useful in treating AD and other skin diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

A role for inflammatory mediators in heterologous desensitization of CysLT1 receptor in human monocytes

PubMed Central

Capra, Valérie; Accomazzo, Maria Rosa; Gardoni, Fabrizio; Barbieri, Silvia; Rovati, G. Enrico

2010-01-01

Cysteinyl-leukotrienes (cysteinyl-LT) are rapidly generated at sites of inflammation and, in addition to their role in asthma, rhinitis, and other immune disorders, are increasingly regarded as significant inflammatory factors in cancer, gastrointestinal, cardiovascular diseases. We recently demonstrated that in monocyte/macrophage–like U937 cells, extracellular nucleotides heterologously desensitize CysLT1 receptor (CysLT1R)-induced Ca2+ transients. Given that monocytes express a number of other inflammatory and chemoattractant receptors, this study was aimed at characterizing transregulation between these different stimuli. We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating Gi-coupled receptor (FPR1, BLT1) desensitize CysLT1R-induced Ca2+ response unidirectionally through activation of PKC. Conversely, PAF-R, exclusively coupled to Gq, cross-desensitizes CysLT1R without the apparent involvement of any kinase. Interestingly, Gs-coupled receptors (β2AR, H1/2R, EP2/4R) are also able to desensitize CysLT1R response through activation of PKA. Heterologous desensitization seems to affect mostly the Gi-mediated signaling of the CysLT1R. The hierarchy of desensitization among agonists may be important for leukocyte signal processing at the site of inflammation. Considering that monocytes/macrophages are likely to be the major source of cysteinyl-LT in many immunological and inflammatory processes, shedding light on how their receptors are regulated will certainly help to better understand the role of these cells in orchestrating this complex network of integrated signals. PMID:19965602

Frontiers in Drug Research and Development for Inflammatory Bowel Disease

PubMed Central

Currò, Diego; Pugliese, Daniela; Armuzzi, Alessandro

2017-01-01

Inflammatory bowel disease (IBD) is idiopathic, lifelong, immune-mediated diseases, for which curative therapies are not yet available. In the last 15 years, the introduction of monoclonal antibodies targeting tumor necrosis factor-α, a cytokine playing a key role in bowel inflammation, has revolutionized treatment paradigms for IBD. Despite their proven long-term efficacy, however, many patients do not respond or progressively lose response to these drugs. Major advances of knowledge in immunology and pathophysiology of intestinal inflammatory processes have made possible the identification of new molecular targets for drugs, thus opening several new potential therapeutic opportunities for IBD. The abnormal response of intestinal immunity to unknown antigens leads to the activation of T helper lymphocytes and triggers the inflammatory cascade. Sphingosine 1-phosphate receptor agonists negatively modulate the egress of lymphocytes, inducted by antigen-presenting cells, from secondary lymphoid tissues to intestinal wall. Leukocyte adhesion inhibitors (both anti-integrin and anti-Mucosal Vascular Addressin Cell Adhesion Molecule 1) interfere with the tissue homing processes. Activated T helper lymphocytes increase the levels of pro-inflammatory cytokines, such as interleukin 12, 23, and 6, offering several potential pharmacological interventions. The Janus kinases, intracellular enzymes mediating the transduction of several cytokine signals, are other explored targets for treating immune-mediated diseases. Finally, the impact of modulating Smad7 pathway, which is responsible for the down-regulation of the immunosuppressive cytokine transforming growth factor-β signaling, is currently under investigation. The purpose of this review is to discuss the most promising molecules in late-stage clinical development, with a special emphasis on pharmacological properties. PMID:28690543

[Inflammatory process in atherogenesis: new facts about old flame].

PubMed

Vucević, Danijela; Radak, Dorde; Radosavljević, Tatjana; Mladenović, Dusan; Milovanović, Ivan

2012-01-01

INTRODUCTION. Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Endothelial Dysfunction and Inflammatory Process. Endothelial dysfunction is recognized as the crucial step in atherogenesis. A lot of studies have confirmed the involvement of various mediators of inflammation in initial proatherogenic processes, such as the upregulation of adhesion molecules on endothelial cells, binding of low density lipoproteins to endothelium, activation of macrophages and proliferation of vascular smooth muscle cells. Fatty stain and Inflammatory Process. Fatty stain consists of foam cell accumulation. After foam cell formation, mediators of inflammation initiate a series ofintracellular events that include the induction of inflammatory cytokines. Thus, a vicious circle of inflammation, modification of lipoproteins and further inflammation can be maintained in the artery. Transitory Lesion and Inflammatory Process. In transitory lesion intensive phagocytosis of oxidized low density lipoproteins additionally activates monocytes and macrophages and consequently facilitates and exacerbates the inflammatory response. Fibrotic Plaque and Inflammatory Process. Inflammatory process, matrix-degrading metalloproteinases activity, platelets aggregation and smooth muscle cells proliferation play a central role in development of fibrotic plaque. Complex Lesion and Inflammatory Process. It has been shown that inflammation is closely related to the development of atherosclerotic plaque rupture. The contribution of inflammatory process has become increasingly meaningful in understanding the initiation, progression and clinical manifestations ofatherosclerosis.

The investigation of anti-inflammatory activity of Yi Guanjian decoction by serum metabonomics approach.

PubMed

Shui, Sufang; Cai, Xiaorong; Huang, Rongqing; Xiao, Bingkun; Yang, Jianyun

2017-01-30

Yi Guanjian (YGJ), one of the Chinese herbal medicines most commonly used in western countries, reported to possess significant anti-inflammatary effects that inhibit the process of inflammation. However, the mechanisms underlying its anti-inflammation effects remain largely unresolved. This study was aimed to investigate the anti-inflammatory activity of YGJ and to explore its potential anti-inflammatory mechanisms by serum metabonomics approach. An xylene-induced mouse right-ear-edema model was used as an inflammatory response in vivo model. Ear edema, prostaglandin E2 (PGE 2 ) and Tumor-Necrosis-Factor-alpha (TNF-α) were detected. Then, serum metabolic profiling was analyzed and pathway analysis performed on the biomarkers reversed after YGJ administration and further integration of metabolic networks. The results showed that YGJ alleviated ear edema and decreased serum PGE 2 and TNF-α levels. Fourteen biomarkers were screened, and the levels were all reversed to different degrees after YGJ administration. These biomarkers were mainly related to linoleic acid metabolism, taurine and hypotaurine metabolism, glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism and citrate cycle (TCA cycle). In metabolic networks, glycine and pyruvate were node molecules. This indicated that YGJ could significantly inhibit inflammatory response triggered by acute local stimulation and exerted anti-inflammatory activity mainly by regulating node molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88.

PubMed

Into, Takeshi; Horie, Toshi; Inomata, Megumi; Gohda, Jin; Inoue, Jun-Ichiro; Murakami, Yukitaka; Niida, Shumpei

2017-04-21

Autophagy, the processes of delivery of intracellular components to lysosomes, regulates induction of inflammation. Inducible macroautophagy degrades inflammasomes and dysfunctional mitochondria to downregulate inflammatory signals. Nonetheless, the effects of constitutive basal autophagy on inflammatory signals are largely unknown. Here, we report a previously unknown effect of basal autophagy. Lysosomal inhibition induced weak inflammatory signals in the absence of a cellular stimulus and in the presence of a nutrient supply, and their induction was impaired by MyD88 deficiency. During lysosomal inhibition, MyD88 was accumulated, and overabundant MyD88 autoactivated downstream signaling or enhanced TLR/IL-1R-mediated signaling. MyD88 is probably degraded via basal microautophagy because macroautophagy inhibitors, ATG5 deficiency, and an activator of chaperone-mediated autophagy did not affect MyD88. Analysis using a chimeric protein whose monomerization/dimerization can be switched revealed that monomeric MyD88 is susceptible to degradation. Immunoprecipitation of monomeric MyD88 revealed its interaction with TRAF6. In TRAF6-deficient cells, degradation of basal MyD88 was enhanced, suggesting that TRAF6 participates in protection from basal autophagy. Thus, basal autophagy lowers monomeric MyD88 expression, and thereby autoactivation of inflammatory signals is prevented. Given that impairment of lysosomes occurs in various settings, our results provide novel insights into the etiology of inflammatory signals that affect consequences of inflammation.

The orphan nuclear receptor TLX regulates hippocampal transcriptome changes induced by IL-1β.

PubMed

Ó'Léime, Ciarán S; Hoban, Alan E; Hueston, Cara M; Stilling, Roman; Moloney, Gerard; Cryan, John F; Nolan, Yvonne M

2018-05-01

TLX is an orphan nuclear receptor highly expressed within neural progenitor cells (NPCs) in the hippocampus where is regulates proliferation. Inflammation has been shown to have negative effects on hippocampal function as well as on NPC proliferation. Specifically, the pro-inflammatory cytokine IL-1β suppresses NPC proliferation as well as TLX expression in the hippocampus. However, it is unknown whether TLX itself is involved in regulating the inflammatory response in the hippocampus. To explore the role of TLX in inflammation, we assessed changes in the transcriptional landscape of the hippocampus of TLX knockout mice (TLX -/- ) compared to wildtype (WT) littermate controls with and without intrahippocampal injection of IL-1β using a whole transcriptome RNA sequencing approach. We demonstrated that there is an increase in the transcription of genes involved in the promotion of inflammation and regulation of cell chemotaxis (Tnf, Il1b, Cxcr1, Cxcr2, Tlr4) and a decrease in the expression of genes relating to synaptic signalling (Lypd1, Syt4, Cplx2) in cannulated TLX -/- mice compared to WT controls. We demonstrate that mice lacking in TLX share a similar increase in 176 genes involved in regulating inflammation (e.g. Cxcl1, Tnf, Il1b) as WT mice injected with IL-1β into the hippocampus. Moreover, TLX -/- mice injected with IL-1β displayed a blunted transcriptional profile compared to WT mice injected with IL-1β. Thus, TLX -/- mice, which already have an exaggerated inflammatory profile after cannulation surgery, are primed to respond differently to an inflammatory stimulus such as IL-1β. Together, these results demonstrate that TLX regulates hippocampal inflammatory transcriptome response to brain injury (in this case cannulation surgery) and cytokine stimulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Microstructured Titanium Regulates Interleukin Production by Osteoblasts, an Effect Modulated by Exogenous BMP-2

PubMed Central

Hyzy, Sharon; Olivares-Navarrete, Rene; Hutton, Daphne L.; Tan, Christian; Boyan, Barbara D.; Schwartz, Zvi

2013-01-01

Microtextured implant surfaces increase osteoblast differentiation in vitro and enhance bone-to-implant contact in vivo and clinically. These implants may be used in combination with recombinant human bone morphogenetic protein 2 (rhBMP-2) to enhance peri-implant bone formation. However, the effect of surface modifications alone or in combination with rhBMP-2 on osteoblast-produced inflammatory microenvironment is unknown. MG63 cells were cultured on tissue culture polystyrene or titanium substrates: smooth pretreated (PT, Ra=0.2μm), sandblasted/acid-etched (SLA, Ra=3.2μm), or hydrophilic-SLA (modSLA). Expression and protein production of pro-inflammatory interleukins (IL1b, IL6, IL8, IL17) and anti-inflammatory interleukins (IL10) were measured in cells with or without rhBMP-2. To determine which BMP signaling pathways were involved, cultures were incubated with BMP pathway inhibitors to blocking Smad (dorsomorphin), TAB/TAK1 ((5Z)-7-oxozeaenol), or PKA (H-8) signaling. Culture on rough SLA and modSLA surfaces decreased pro-inflammatory interleukins and increased anti-inflammatory IL10. This effect was negated in cells treated with rhBMP-2, which caused an increase in pro-inflammatory interleukins and a decrease in anti-inflammatory interleukins through TAB/TAK signaling. The results suggest that surface microtexture modulates the inflammatory process during osseointegration, an effect that may enhance healing. However, rhBMP-2 in combination with microtextured titanium implants can influence the effect of cells on these surfaces, and may adversely affect cells involved in osseointegration. PMID:23123301

Lactoferrin and oral diseases: current status and perspective in periodontitis

PubMed Central

Berlutti, Francesca; Pilloni, Andrea; Pietropaoli, Miriam; Polimeni, Antonella; Valenti, Piera

2012-01-01

Summary Lactoferrin (Lf), an iron-binding glycoprotein able to chelate two ferric ions per molecule, is a component of human secretions synthesized by exocrine glands and neutrophils in infection/inflammation sites. Lactoferrin in saliva represents an important defence factor against bacterial injuries including those related to Streptococcus mutans and periodontopathic bacteria through its ability to decrease bacterial growth, biofilm development, iron overload, reactive oxygen formation and inflammatory processes. A growing body of research suggests that inflammatory periodontal disease involves a failure of resolution pathways to restore tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution involves biologic pathways restoring inflammatory homeostasis. An appropriate regulation of pro-inflammatory cytokine synthesis might be useful in reducing periodontal tissue destruction. Recently, the multi-functional IL-6 is emerging as an important factor able to modulate bone, iron and inflammatory homeostasis. Here, we report an overview of Lf functions as well as for the first time Lf anti-inflammatory ability against periodontitis in in vitro model and observational clinical study. In in vitro model, represented by gingival fibroblasts infected with Prevotella intermedia, Lf exerted a potent anti-inflammatory activity. In the observational clinical trial performed through bovine Lf (bLf) topically administered to volunteers suffering from periodontitis, bLf decreased cytokines, including IL-6 in crevicular fluid, edema, bleeding, pocket depth, gingival and plaque index, thus improving clinical attachment levels. Even if other clinical trials are required, these results provide strong evidence for a instead of an therapeutic potential of this multifunctional natural protein. PMID:22545184

East Indian Sandalwood Oil Is a Phosphodiesterase Inhibitor: A New Therapeutic Option in the Treatment of Inflammatory Skin Disease.

PubMed

Sharma, Manju; Levenson, Corey; Browning, John C; Becker, Emily M; Clements, Ian; Castella, Paul; Cox, Michael E

2018-01-01

Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score. EISO treatment of a psoriasis model reduced PDE4 expression and reversed histopathology. EISO directly inhibited PDE enzymatic activity in vitro . In lipopolysaccharide-stimulated human dermal fibroblast, BEAS-2B, A549, and THP-1 cells, EISO suppressed total cellular PDE activity, PDE4, and 7 transcript levels, nuclear factor kappa B (NF-κB) activation, and pro-inflammatory cytokines/chemokine production. These results suggest that EISO anti-inflammatory activity is mediated through suppressing PDE activity, thus facilitating cAMP-regulated inhibition of NF-κB and indicate EISO as an attractive natural therapeutic for chronic and acute inflammatory disorders.

East Indian Sandalwood Oil Is a Phosphodiesterase Inhibitor: A New Therapeutic Option in the Treatment of Inflammatory Skin Disease

PubMed Central

Sharma, Manju; Levenson, Corey; Browning, John C.; Becker, Emily M.; Clements, Ian; Castella, Paul; Cox, Michael E.

2018-01-01

Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score. EISO treatment of a psoriasis model reduced PDE4 expression and reversed histopathology. EISO directly inhibited PDE enzymatic activity in vitro. In lipopolysaccharide-stimulated human dermal fibroblast, BEAS-2B, A549, and THP-1 cells, EISO suppressed total cellular PDE activity, PDE4, and 7 transcript levels, nuclear factor kappa B (NF-κB) activation, and pro-inflammatory cytokines/chemokine production. These results suggest that EISO anti-inflammatory activity is mediated through suppressing PDE activity, thus facilitating cAMP-regulated inhibition of NF-κB and indicate EISO as an attractive natural therapeutic for chronic and acute inflammatory disorders. PMID:29593534

C/EBPβ is a transcriptional key regulator of IL-36α in murine macrophages.

PubMed

Nerlich, Andreas; Ruangkiattikul, Nanthapon; Laarmann, Kristin; Janze, Nina; Dittrich-Breiholz, Oliver; Kracht, Michael; Goethe, Ralph

2015-08-01

Interleukin (IL)-36α - one of the novel members of the IL-1 family of cytokines - is a potent regulator of dendritic and T cells and plays an important role in inflammatory processes like experimental skin inflammation in mice and in mouse models for human psoriasis. Here, we demonstrate that C/EBPβ, a transcription factor required for the selective expression of inflammatory genes, is a key activator of the Il36A gene in murine macrophages. RNAi-mediated suppression of C/EBPβ expression in macrophages (C/EBPβ(low) cells) significantly impaired Il36A gene induction following challenge with LPS. Despite the presence of five predicted C/EBP binding sites, luciferase reporter assays demonstrated that C/EBPβ confers responsiveness to LPS primarily through a half-CRE•C/EBP element in the proximal Il36A promoter. Electrophoretic mobility shift assays showed that C/EBPβ but not CREB proteins interact with this critical half-CRE•C/EBP element. In addition, overexpression of C/EBPβ in C/EBPβ(low) cells enhanced the expression of Il36A whereas CREB-1 had no effect. Finally, chromatin immunoprecipitation confirmed that C/EBPβ but neither CREB-1, ATF-2 nor ATF4 is directly recruited to the proximal promoter region of the Il36A gene. Together, these findings demonstrate an essential role of C/EBPβ in the regulation of the Il36A gene via the proximal half-CRE•C/EBP element in response to inflammatory stimuli. Copyright © 2015 Elsevier B.V. All rights reserved.

Cytokine networking of innate immunity cells: a potential target of therapy.

PubMed

Striz, Ilja; Brabcova, Eva; Kolesar, Libor; Sekerkova, Alena

2014-05-01

Innate immune cells, particularly macrophages and epithelial cells, play a key role in multiple layers of immune responses. Alarmins and pro-inflammatory cytokines from the IL (interleukin)-1 and TNF (tumour necrosis factor) families initiate the cascade of events by inducing chemokine release from bystander cells and by the up-regulation of adhesion molecules required for transendothelial trafficking of immune cells. Furthermore, innate cytokines produced by dendritic cells, macrophages, epithelial cells and innate lymphoid cells seem to play a critical role in polarization of helper T-cell cytokine profiles into specific subsets of Th1/Th2/Th17 effector cells or regulatory T-cells. Lastly, the innate immune system down-regulates effector mechanisms and restores homoeostasis in injured tissue via cytokines from the IL-10 and TGF (transforming growth factor) families mainly released from macrophages, preferentially the M2 subset, which have a capacity to induce regulatory T-cells, inhibit the production of pro-inflammatory cytokines and induce healing of the tissue by regulating extracellular matrix protein deposition and angiogenesis. Cytokines produced by innate immune cells represent an attractive target for therapeutic intervention, and multiple molecules are currently being tested clinically in patients with inflammatory bowel disease, rheumatoid arthritis, systemic diseases, autoinflammatory syndromes, fibrosing processes or malignancies. In addition to the already widely used blockers of TNFα and the tested inhibitors of IL-1 and IL-6, multiple therapeutic molecules are currently in clinical trials targeting TNF-related molecules [APRIL (a proliferation-inducing ligand) and BAFF (B-cell-activating factor belonging to the TNF family)], chemokine receptors, IL-17, TGFβ and other cytokines.

A flame burning within.

PubMed

Ferrucci, Luigi; Ble, Alessandro; Bandinelli, Stefania; Lauretani, Fulvio; Suthers, Kristen; Guralnik, Jack M

2004-06-01

Inflammation is a human being's primary defense against threats to homeostasis that are encountered every day. Especially in old age, when regulatory mechanisms responsible for inflammatory responses may be ineffective or damaged, the result can be adverse pathological conditions, and an increased risk of morbidity and mortality. The inflammation response is a plastic network composed of redundant signaling among several different mediators. These mediators have a reciprocal relationship with other biological sub-systems, including hormone regulation, the autonomic nervous system, and oxidative/anti-oxidant balance. Studying this complex architecture requires parallel and multiple research strategies from epidemiological to biochemical level, from observational studies to innovative intervention approaches. Given that the inflammatory response is a critical age-related process, understanding its regulatory action is essential in avoiding hazardous consequences in old age.

Noncoding RNAs and chronic inflammation: Micro-managing the fire within.

PubMed

Alexander, Margaret; O'Connell, Ryan M

2015-09-01

Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age-associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. © 2015 The Authors. BioEssays published by WILEY Periodicals, Inc.

AhR-deficiency as a cause of demyelinating disease and inflammation.

PubMed

Juricek, Ludmila; Carcaud, Julie; Pelhaitre, Alice; Riday, Thorfinn T; Chevallier, Aline; Lanzini, Justine; Auzeil, Nicolas; Laprévote, Olivier; Dumont, Florent; Jacques, Sebastien; Letourneur, Frank; Massaad, Charbel; Agulhon, Cendra; Barouki, Robert; Beraneck, Mathieu; Coumoul, Xavier

2017-08-29

The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.

Age-Dependent Neurochemical Remodeling of Hypothalamic Astrocytes.

PubMed

Santos, Camila Leite; Roppa, Paola Haack Amaral; Truccolo, Pedro; Fontella, Fernanda Urruth; Souza, Diogo Onofre; Bobermin, Larissa Daniele; Quincozes-Santos, André

2017-10-04

The hypothalamus is a crucial integrative center in the central nervous system, responsible for the regulation of homeostatic activities, including systemic energy balance. Increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions; they participate in the modulation of synaptic transmission, metabolic and trophic support to neurons, immune defense, and nutrient sensing. In this context, disturbance of systemic energy homeostasis, which is a common feature of obesity and the aging process, involves inflammatory responses. This may be related to dysfunction of hypothalamic astrocytes. In this regard, the aim of this study was to evaluate the neurochemical properties of hypothalamic astrocyte cultures from newborn, adult, and aged Wistar rats. Age-dependent changes in the regulation of glutamatergic homeostasis, glutathione biosynthesis, amino acid profile, glucose metabolism, trophic support, and inflammatory response were observed. Additionally, signaling pathways including nuclear factor erythroid-derived 2-like 2/heme oxygenase-1 p38 mitogen-activated protein kinase, nuclear factor kappa B, phosphatidylinositide 3-kinase/Akt, and leptin receptor expression may represent putative mechanisms associated with the cellular alterations. In summary, our findings indicate that as age increases, hypothalamic astrocytes remodel and exhibit changes in their neurochemical properties. This process may play a role in the onset and/or progression of metabolic disorders.

Redox Stimulation of Human THP-1 Monocytes in Response to Cold Physical Plasma.

PubMed

Bekeschus, Sander; Schmidt, Anke; Bethge, Lydia; Masur, Kai; von Woedtke, Thomas; Hasse, Sybille; Wende, Kristian

2016-01-01

In plasma medicine, cold physical plasma delivers a delicate mixture of reactive components to cells and tissues. Recent studies suggested a beneficial role of cold plasma in wound healing. Yet, the biological processes related to the redox modulation via plasma are not fully understood. We here used the monocytic cell line THP-1 as a model to test their response to cold plasma in vitro. Intriguingly, short term plasma treatment stimulated cell growth. Longer exposure only modestly compromised cell viability but apparently supported the growth of cells that were enlarged in size and that showed enhanced metabolic activity. A significantly increased mitochondrial content in plasma treated cells supported this notion. On THP-1 cell proteome level, we identified an increase of protein translation with key regulatory proteins being involved in redox regulation (hypoxia inducible factor 2α), differentiation (retinoic acid signaling and interferon inducible factors), and cell growth (Yin Yang 1). Regulation of inflammation is a key element in many chronic diseases, and we found a significantly increased expression of the anti-inflammatory heme oxygenase 1 (HMOX1) and of the neutrophil attractant chemokine interleukin-8 (IL-8). Together, these results foster the view that cold physical plasma modulates the redox balance and inflammatory processes in wound related cells.

Biomaterials trigger endothelial cell activation when co-incubated with human whole blood.

PubMed

Herklotz, Manuela; Hanke, Jasmin; Hänsel, Stefanie; Drichel, Juliane; Marx, Monique; Maitz, Manfred F; Werner, Carsten

2016-10-01

Endothelial cell activation resulting from biomaterial contact or biomaterial-induced blood activation may in turn also affect hemostasis and inflammatory processes in the blood. Current in vitro hemocompatibility assays typically ignore these modulating effects of the endothelium. This study describes a co-incubation system of human whole blood, biomaterial and endothelial cells (ECs) that was developed to overcome this limitation. First, human endothelial cells were characterized in terms of their expression of coagulation- and inflammation-relevant markers in response to various activators. Subsequently, their capacity to regulate hemostasis as well as complement and granulocyte activation was monitored in a hemocompatibility assay. After blood contact, quiescent ECs exhibited anticoagulant and anti-inflammatory properties. When they were co-incubated with surfaces exhibiting pro-coagulant or pro-inflammatory characteristics, the ECs down-regulated coagulation but not complement or leukocyte activation. Analysis of intracellular levels of the endothelial activation markers E-selectin and tissue factor showed that co-incubation with model surfaces and blood significantly increased the activation state of ECs. Finally, the coagulation- and inflammation-modulating properties of the ECs were tested after blood/biomaterial exposure. Pre-activation of ECs by biomaterials in the blood induced a pro-coagulant and pro-inflammatory state of the ECs, wherein the pro-coagulant response was higher for biomaterial/blood pre-activated ECs than for TNF-α-pre-activated cells. This work provides evidence that biomaterials, even without directly contacting the endothelium, affect the endothelial activation state with and have consequences for plasmatic and cellular reactions in the blood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inositol-C2-PAF down-regulates components of the antigen presentation machinery in a 2D-model of epidermal inflammation.

PubMed

Semini, Geo; Hildmann, Annette; Klein, Andreas; Lucka, Lothar; Schön, Margarete; Schön, Michael P; Shmanai, Vadim; Danker, Kerstin

2014-02-01

In cutaneous inflammatory diseases, such as psoriasis, atopic dermatitis and allergic contact dermatitis, skin-infiltrating T lymphocytes and dendritic cells modulate keratinocyte function via the secretion of pro-inflammatory cytokines. Keratinocytes then produce mediators that recruit and activate immune cells and amplify the inflammatory response. These pathophysiological tissue changes are caused by altered gene expression and the proliferation and maturation of dermal and epidermal cells. We recently demonstrated that the glycosidated phospholipid Ino-C2-PAF down-regulates a plethora of gene products associated with innate and acquired immune responses and inflammation in the HaCaT keratinocyte cell line. To further evaluate the influence of Ino-C2-PAF we established an in vitro 2D-model of epidermal inflammation. The induction of inflammation and the impact of Ino-C2-PAF were assessed in this system using a genome-wide microarray analysis. In addition, the expression of selected genes was validated using qRT-PCR and flow cytometry. Treatment of the keratinocytes with a mix of proinflammatory cytokines resulted in transcriptional effects on a variety of genes involved in cutaneous inflammation and immunity, while additional treatment with Ino-C2-PAF counteracted the induction of many of these genes. Remarkably, Ino-C2-PAF suppressed the expression of a group of targets that are implicated in antigen processing and presentation, including MHC molecules. Thus, it is conceivable that Ino-C2-PAF possess therapeutic potential for inflammatory skin disorders, such as psoriasis and allergic contact dermatitis. Copyright © 2013 Elsevier Inc. All rights reserved.

Strychnine inhibits inflammatory angiogenesis in mice via down regulation of VEGF, TNF-α and TGF-β.

PubMed

Saraswati, Sarita; Agarwal, S S

2013-05-01

Strychnine is known to possess anti-inflammatory and antitumour activity, but its roles in tumour angiogenesis, the key step involved in tumour growth and metastasis, and the involved molecular mechanism are still unknown. We aimed to investigate the effects of strychnine on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and strychnine (0.25, and 0.5 mg/kg/day) was given through installed cannulas for 9 days. The implants collected at day 9 postimplantation were processed for the assessment of haemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Strychnine treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and transforming growth factor (TGF-β). A regulatory function of strychnine on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of strychnine. Copyright © 2013 Elsevier Inc. All rights reserved.

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

PubMed

Eising, Else; Shyti, Reinald; 't Hoen, Peter A C; Vijfhuizen, Lisanne S; Huisman, Sjoerd M H; Broos, Ludo A M; Mahfouz, Ahmed; Reinders, Marcel J T; Ferrari, Michel D; Tolner, Else A; de Vries, Boukje; van den Maagdenberg, Arn M J M

2017-05-01

Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α 1A subunit of voltage-gated Ca V 2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.

The fundamental role of mechanical properties in the progression of cancer disease and inflammation

NASA Astrophysics Data System (ADS)

Mierke, Claudia Tanja

2014-07-01

The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in particular the understanding of mechano-coupling and mechano-regulating functions in cell invasion, appears as an important step in cancer progression and inflammatory response to injuries. This may lead to novel insights into cancer disease and inflammatory diseases and will overcome classical views on cancer and inflammation. In addition, this review will discuss how the physics of cancer and inflammation can help to reveal whether cancer cells will invade connective tissue and metastasize or how leukocytes extravasate and migrate through the tissue. In this review, the physical concepts of cancer progression, including the tissue basement membrane a cancer cell is crossing, its invasion and transendothelial migration as well as the basic physical concepts of inflammatory processes and the cellular responses to the mechanical stress of the microenvironment such as external forces and matrix stiffness, are presented and discussed. In conclusion, this review will finally show how physical measurements can improve classical approaches that investigate cancer and inflammatory diseases, and how these physical insights can be integrated into classical tumor biological approaches.

Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases.

PubMed

Cronstein, Bruce N; Sitkovsky, Michail

2017-01-01

Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed.

Bile acid regulates c-Jun expression through the orphan nuclear receptor SHP induction in gastric cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Won Il; Park, Min Jung; An, Jin Kwang

2008-05-02

Bile reflux is considered to be one of the most important causative factors in gastric carcinogenesis, due to the attendant inflammatory changes in the gastric mucosa. In this study, we have assessed the molecular mechanisms inherent to the contribution of bile acid to the transcriptional regulation of inflammatory-related genes. In this study, we demonstrated that bile acid induced the expression of the SHP orphan nuclear receptor at the transcriptional level via c-Jun activation. Bile acid also enhanced the protein interaction of NF-{kappa}B and SHP, thereby resulting in an increase in c-Jun expression and the production of the inflammatory cytokine, TNF{alpha}.more » These results indicate that bile acid performs a critical function in the regulation of the induction of inflammatory-related genes in gastric cells, and that bile acid-mediated gene expression provides a pre-clue for the development of gastric cellular malformation.« less

A Primary Human Trophoblast Model to Study the Effect of Inflammation Associated with Maternal Obesity on Regulation of Autophagy in the Placenta.

PubMed

Simon, Bailey; Bucher, Matthew; Maloyan, Alina

2017-09-27

Maternal obesity is associated with an increased risk of adverse perinatal outcomes that are likely mediated by compromised placental function that can be attributed to, in part, the dysregulation of autophagy. Aberrant changes in the expression of autophagy regulators in the placentas from obese pregnancies may be regulated by inflammatory processes associated with both obesity and pregnancy. Described here is a protocol for sampling of villous tissue and isolation of villous cytotrophoblasts from the term human placenta for primary cell culture. This is followed by a method for simulating the inflammatory milieu in the obese intrauterine environment by treating primary trophoblasts from lean pregnancies with tumor necrosis factor alpha (TNFα), a proinflammatory cytokine that is elevated in obesity and in pregnancy. Through the implementation of the protocol described here, it is found that exposure to exogenous TNFα regulates the expression of Rubicon, a negative regulator of autophagy, in trophoblasts from lean pregnancies with female fetuses. While a variety of biological factors in the obese intrauterine environment maintain the potential to modulate critical pathways in trophoblasts, this ex vivo system is especially useful for determining if expression patterns observed in vivo in human placentas with maternal obesity are a direct result of TNFα signaling. Ultimately, this approach affords the opportunity to parse out the regulatory and molecular implications of inflammation associated with maternal obesity on autophagy and other critical cellular pathways in trophoblasts that have the potential to impact placental function.

Mitogen-Activated Protein Kinase 2 Signaling Shapes Macrophage Plasticity in Aggregatibacter actinomycetemcomitans-Induced Bone Loss

PubMed Central

Herbert, Bethany A.; Steinkamp, Heidi M.; Gaestel, Matthias

2016-01-01

ABSTRACT Aggregatibacter actinomycetemcomitans is associated with aggressive periodontal disease, which is characterized by inflammation-driven alveolar bone loss. A. actinomycetemcomitans activates the p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) stress pathways in macrophages that are involved in host responses. During the inflammatory process in periodontal disease, chemokines are upregulated to promote recruitment of inflammatory cells. The objective of this study was to determine the role of MK2 signaling in chemokine regulation during A. actinomycetemcomitans pathogenesis. Utilizing a murine calvarial model, Mk2+/+ and Mk2−/− mice were treated with live A. actinomycetemcomitans bacteria at the midsagittal suture. MK2 positively regulated the following macrophage RNA: Emr1 (F4/80), Itgam (CD11b), Csf1r (M-CSF Receptor), Itgal (CD11a), Tnf, and Nos2. Additionally, RNA analysis revealed that MK2 signaling regulated chemokines CCL3 and CCL4 in murine calvarial tissue. Utilizing the chimeric murine air pouch model, MK2 signaling differentially regulated CCL3 and CCL4 in the hematopoietic and nonhematopoietic compartments. Bone resorption pits in calvaria, observed by micro-computed tomography, and osteoclast formation were decreased in Mk2−/− mice compared to Mk2+/+ mice after A. actinomycetemcomitans treatment. In conclusion, these data suggest that MK2 in macrophages contributes to regulation of chemokine signaling during A. actinomycetemcomitans-induced inflammation and bone loss. PMID:27795356

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

PubMed

Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

2017-06-01

Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

C/EBP beta regulation of the tumor necrosis factor alpha gene.

PubMed Central

Pope, R M; Leutz, A; Ness, S A

1994-01-01

Activated macrophages contribute to chronic inflammation by the secretion of cytokines and proteinases. Tumor necrosis factor alpha (TNF alpha) is particularly important in this process because of its ability to regulate other inflammatory mediators in an autocrine and paracrine fashion. The mechanism(s) responsible for the cell type-specific regulation of TNF alpha is not known. We present data to show that the expression of TNF alpha is regulated by the transcription factor C/EBP beta (NF-IL6). C/EBP beta activated the TNF alpha gene promoter in cotransfection assays and bound to it at a site which failed to bind the closely related protein C/EBP alpha. Finally, a dominant-negative version of C/EBP beta blocked TNF alpha promoter activation in myeloid cells. Our results implicate C/EBP beta as an important regulator of TNF alpha by myelomonocytic cells. Images PMID:7929820

Silymarin prevents NLRP3 inflammasome activation and protects against intracerebral hemorrhage.

PubMed

Yuan, Raorao; Fan, Hengyi; Cheng, Shiqi; Gao, WeiWei; Xu, Xin; Lv, Shigang; Ye, Minhua; Wu, Miaojing; Zhu, Xingen; Zhang, Yan

2017-09-01

Inflammatory response mediates secondary injury during intracerebral hemorrhage (ICH). In the present study, we determined oxidative stress and involvement of NLRP3 in ICH injury and analyzed whether silymarin might offer protective effect against ICH injury. Post 24h after ICH injury there was increased oxidative stress markers (reactive oxygen species (ROS) and lipid peroxides) compared to sham group. Silymarin (200mg/kg) treatment 30 mins post ICH injury prevented increase in oxidative stress markers and up-regulated antioxidant status. Further, there was significant increase in nuclear levels of NF-κB-p65 and pro-inflammatory cytokine expressions post ICH injury. NLRP3 inflammasome activation and downstream targets such as caspase-1 and IL-1β expressions were significantly up regulated in ICH injury. Silymarin treatment significantly down regulated the inflammatory responses by suppressing NF-κB-p65 levels and inflammasome-mediated caspase-1/IL-1β expressions. Further, treatment with silymarin post ICH injury increased Nrf-2/HO-1 and thereby improved overall cytoprotection. These findings together show that silymarin acts as neuroprotective compound by preventing inflammatory activation and up regulating Nrf-2/HO-1 signaling post ICH injury. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Crosstalk between Oxidative Stress and SIRT1: Impact on the Aging Process

PubMed Central

Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

2013-01-01

Increased oxidative stress has been associated with the aging process. However, recent studies have revealed that a low-level oxidative stress can even extend the lifespan of organisms. Reactive oxygen species (ROS) are important signaling molecules, e.g., being required for autophagic degradation. SIRT1, a class III protein deacetylase, is a crucial cellular survival protein, which is also involved in combatting oxidative stress. For instance, SIRT1 can stimulate the expression of antioxidants via the FoxO pathways. Moreover, in contrast to ROS, SIRT1 inhibits NF-κB signaling which is a major inducer of inflammatory responses, e.g., with inflammasome pathway. Recent studies have demonstrated that an increased level of ROS can both directly and indirectly control the activity of SIRT1 enzyme. For instance, ROS can inhibit SIRT1 activity by evoking oxidative modifications on its cysteine residues. Decreased activity of SIRT1 enhances the NF-κB signaling, which supports inflammatory responses. This crosstalk between the SIRT1 and ROS signaling provokes in a context-dependent manner a decline in autophagy and a low-grade inflammatory phenotype, both being common hallmarks of ageing. We will review the major mechanisms controlling the signaling balance between the ROS production and SIRT1 activity emphasizing that this crosstalk has a crucial role in the regulation of the aging process. PMID:23434668

The bromodomain protein BRD4 regulates splicing during heat shock

PubMed Central

Hussong, Michelle; Kaehler, Christian; Kerick, Martin; Grimm, Christina; Franz, Alexandra; Timmermann, Bernd; Welzel, Franziska; Isensee, Jörg; Hucho, Tim; Krobitsch, Sylvia; Schweiger, Michal R.

2017-01-01

The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies. PMID:27536004

The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases.

PubMed

Hassa, Paul O; Hottiger, Michael O

2008-01-01

Poly-ADP-ribose metabolism plays a mayor role in a wide range of biological processes, such as maintenance of genomic stability, transcriptional regulation, energy metabolism and cell death. Poly-ADP-ribose polymerases (PARPs) are an ancient family of enzymes, as evidenced by the poly-ADP-ribosylating activities reported in dinoflagellates and archaebacteria and by the identification of Parp-like genes in eubacterial and archaeabacterial genomes. Six genes encoding "bona fide" PARP enzymes have been identified in mammalians: PARP1, PARP2, PARP3, PARP4/vPARP, PARP5/Tankyrases-1 and PARP6/Tankyrases-2. The best studied of these enzymes PARP1 plays a primary role in the process of poly-ADP-ribosylation. PARP1-mediated poly-ADP-ribosylation has been implicated in the pathogenesis of cancer, inflammatory and neurodegenerative disorders. This review will summarize the novel findings and concepts for PARP enzymes and their poly-ADP-ribosylation activity in the regulation of physiological and pathophysiological processes. A special focus is placed on the proposed molecular mechanisms involved in these processes, such as signaling, regulation of telomere dynamics, remodeling of chromatin structure and transcriptional regulation. A potential functional cross talk between PARP family members and other NAD+-consuming enzymes is discussed.

Role of interleukin-22 in inflammatory bowel disease.

PubMed

Li, Lin-Jing; Gong, Chen; Zhao, Mei-Hua; Feng, Bai-Sui

2014-12-28

Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.

Mechanisms of Toll-like receptor 4 endocytosis reveal a common immune-evasion strategy used by pathogenic and commensal bacteria

PubMed Central

Tan, Yunhao; Zanoni, Ivan; Cullen, Thomas W.; Goodman, Andrew L.; Kagan, Jonathan C.

2015-01-01

Microbe-induced receptor trafficking has emerged as an essential means to promote innate immune signal transduction. Upon detection of bacterial lipopolysaccharides (LPS), CD14 induces an inflammatory endocytosis pathway that delivers Toll-like Receptor 4 (TLR4) to endosomes. Although several regulators of CD14-dependent TLR4 endocytosis have been identified, the cargo selection mechanism during this process remains unknown. We reveal that, in contrast to classic cytosolic interactions that promoted the endocytosis of transmembrane receptors, TLR4 was selected as cargo for inflammatory endocytosis entirely through extracellular interactions. Mechanistically, the extracellular protein MD-2 bound to and dimerized TLR4 in order to promote this endocytic event. Our analysis of LPS variants from human pathogens and gut commensals revealed a common mechanism by which bacteria prevent inflammatory endocytosis. We suggest that evasion of CD14-dependent endocytosis is an attribute that transcends the concept of pathogenesis, and may be a fundamental feature of bacteria that inhabit eukaryotic hosts. PMID:26546281

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis

PubMed Central

Lefèvre, Lise; Authier, Hélène; Stein, Sokrates; Majorel, Clarisse; Couderc, Bettina; Dardenne, Christophe; Eddine, Mohamad Ala; Meunier, Etienne; Bernad, José; Valentin, Alexis; Pipy, Bernard; Schoonjans, Kristina; Coste, Agnès

2015-01-01

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis. PMID:25873311

Photoaging and skin cancer: Is the inflammasome the missing link?

PubMed

Awad, Fawaz; Assrawi, Eman; Louvrier, Camille; Jumeau, Claire; Giurgea, Irina; Amselem, Serge; Karabina, Sonia-Athina

2018-03-12

Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)1β and IL18 cytokines, and an inflammatory form of death named pyroptosis. NLRP1 inflammasomes have taken centre stage in skin biology, as mutations in NLRP1 underlie the genetic etiology of dermatological diseases and increase the susceptibility to skin cancer. Targeting inflammasome(s) might be an important approach to improve skin inflammation, photoaging and reduce the risk of epithelial skin tumorigenesis. In this context, we discuss the potential implication of NLRP1 and NLRP3 inflammasomes. Copyright © 2018 Elsevier B.V. All rights reserved.

Regulation of Survival by IKKe in Inflammatory Breast Cancer Involves EpCAM

DTIC Science & Technology

2016-02-01

responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms . Blood. 2010;115(25):5232-40. 29. Duncan JS, Whittle MC, Nakamura K...responses and normalizes inflammatory cytokines in murine myeloprolifer - ative neoplasms . Blood. 2010;115(25):5232–5240. 34. Aref AR, et al. Screening

Cellular and Molecular Players in Adipose Tissue Inflammation in the Development of Obesity-induced Insulin Resistance

PubMed Central

Lee, Byung-Cheol; Lee, Jongsoon

2013-01-01

There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. PMID:23707515

CHP1002, a novel andrographolide derivative, inhibits pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW264.7 macrophages via up-regulation of heme oxygenase-1 expression.

PubMed

Zhang, Bo; Yan, Lingdi; Zhou, Peilan; Dong, Zhaoqi; Feng, Siliang; Liu, Keliang; Gong, Zehui

2013-02-01

Andrographolides, a type of diterpene lactone, are widely known to have anti-inflammatory and anti-oxidative properties. CHP1002, a synthetic derivative of andrographolide, has similar anti-inflammatory action in mouse ear swelling test and rat paw edema test. In the present study, the mechanism of anti-inflammatory effects of CHP1002 was investigated in RAW264.7 macrophages. CHP1002 potently suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CHP1002 reduced the production of iNOS-derived nitric oxide (NO) and COX-2-derived prostaglandin E2 (PGE2). CHP1002 induced heme oxygenase-1 (HO-1) expression via activation of extracellular signal-regulated kinase (ERK) and NF-E2 related factor 2 transcription factor (Nrf2). Down-regulation of LPS-induced iNOS and COX-2 expressions was partially reversed by the HO-1 inhibitor zinc protoporphyrin (ZnPP). In addition, CHP1002 significantly attenuated LPS-induced TNF-α, IL-1β and IL-6 production. CHP1002 effectively induced HO-1 and was capable of inhibiting some macrophage-derived pro-inflammatory mediators, which may be closely correlated with its anti-inflammatory action. Copyright © 2012 Elsevier B.V. All rights reserved.

c-Kit modifies the inflammatory status of smooth muscle cells

PubMed Central

Song, Lei; Martinez, Laisel; Zigmond, Zachary M.; Hernandez, Diana R.; Lassance-Soares, Roberta M.; Selman, Guillermo

2017-01-01

Background c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. Methods High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. Results The microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. Discussion Our study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation. PMID:28626608

c-Kit modifies the inflammatory status of smooth muscle cells.

PubMed

Song, Lei; Martinez, Laisel; Zigmond, Zachary M; Hernandez, Diana R; Lassance-Soares, Roberta M; Selman, Guillermo; Vazquez-Padron, Roberto I

2017-01-01

c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (Kit W/W-v ) and control (Kit +/+ ) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. The microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. Our study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.

AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

PubMed Central

Serban, Andreea Iren; Stanca, Loredana; Geicu, Ovidiu Ionut; Dinischiotu, Anca

2015-01-01

Advanced glycation end products (AGEs) can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293) upon exposure to 200 μg/mL bovine serum albumine (BSA) or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE) and heat shock proteins (HSPs) 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6), HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs–BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells. PMID:26307981

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

PubMed Central

Gharagozloo, Marjan; Gris, Katsiaryna V.; Mahvelati, Tara; Amrani, Abdelaziz; Lukens, John R.; Gris, Denis

2018-01-01

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) associated with inappropriate activation of lymphocytes, hyperinflammatory responses, demyelination, and neuronal damage. In the past decade, a number of biological immunomodulators have been developed that suppress the peripheral immune responses and slow down the progression of the disease. However, once the inflammation of the CNS has commenced, it can cause serious permanent neuronal damage. Therefore, there is a need for developing novel therapeutic approaches that control and regulate inflammatory responses within the CNS. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular regulators of inflammation expressed by many cell types within the CNS. They redirect multiple signaling pathways initiated by pathogens and molecules released by injured tissues. NLR family members include positive regulators of inflammation, such as NLRP3 and NLRC4 and anti-inflammatory NLRs, such as NLRX1 and NLRP12. They exert immunomodulatory effect at the level of peripheral immune responses, including antigen recognition and lymphocyte activation and differentiation. Also, NLRs regulate tissue inflammatory responses. Understanding the molecular mechanisms that are placed at the crossroad of innate and adaptive immune responses, such as NLR-dependent pathways, could lead to the discovery of new therapeutic targets. In this review, we provide a summary of the role of NLRs in the pathogenesis of MS. We also summarize how anti-inflammatory NLRs regulate the immune response within the CNS. Finally, we speculate the therapeutic potential of targeting NLRs in MS. PMID:29403486

Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sun Ae; Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr

2012-09-07

Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), amore » key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-{alpha}. Taken together, PTEN could be a possible downstream regulator of AMPK, and the AMPK-PTEN pathway might be important in the regulation of the inflammatory response in VSMCs.« less

Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism.

PubMed

Jeon, Kye-Im; Xu, Xiangbin; Aizawa, Toru; Lim, Jae Hyang; Jono, Hirofumi; Kwon, Dong-Seok; Abe, Jun-Ichi; Berk, Bradford C; Li, Jian-Dong; Yan, Chen

2010-05-25

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.

Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism

PubMed Central

Jeon, Kye-Im; Xu, Xiangbin; Aizawa, Toru; Lim, Jae Hyang; Jono, Hirofumi; Kwon, Dong-Seok; Berk, Bradford C.; Li, Jian-Dong; Yan, Chen

2010-01-01

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-α–induced NF-κB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-α- or LPS-induced up-regulation of proinflammatory mediators, including TNF-α, IL-1β, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-α- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-κB–dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca2+ regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases. PMID:20448200

Galectin-3 in autoimmunity and autoimmune diseases

PubMed Central

de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola; Luisetto, Roberto; Ghirardello, Anna; Punzi, Leonardo

2015-01-01

Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell–cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte–macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases. PMID:26142116

The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma.

PubMed

Hernández-Ruiz, Eugenia; Toll, Agustí; García-Diez, Irene; Andrades, Evelyn; Ferrandiz-Pulido, Carla; Masferrer, Emili; Yébenes, Mireia; Jaka, Ane; Gimeno, Javier; Gimeno, Ramón; García-Patos, Vicenç; Pujol, Ramón M; Hernández-Muñoz, Inmaculada

2018-03-08

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epigenetic regulation of gene expression may allow tumoral cells to acquire new functions in order to escape from the primary tumor. The aim of this study was to investigate the expression and function of proteins of the Polycomb family of epigenetic regulators in the metastatic process of cSCC. A higher expression of RING1B and EZH2 was detected by immunohistochemistry in a series of primary cSCC tumors that metastasized (MSCCs) when compared with non-metastasizing cSCCs (non-MSCCs). Stable downregulation of RING1B and EZH2 in cSCC cells results in enhanced expression of inflammatory cytokines and activation of the NF-κB signaling pathway. Accordingly, non-MSCCs display higher levels of membranous pS176-inhibitor of NF-kB kinase, and their stroma is enriched in neutrophils and eosinophils when compared with MSCCs. In vitro, hematopoietic cells exhibit a substantial migratory response to supernatants from Polycomb-depleted cSCC cells. Altogether, these data indicate that RING1B and EZH2 repress the innate inflammatory cSCC function and impair tumor immunosurveillance and suggest that patients with high-risk cSCCs could benefit from clinical therapies addressed to harness the immune response.

Regulation of inflammation and redox signaling by dietary polyphenols.

PubMed

Rahman, Irfan; Biswas, Saibal K; Kirkham, Paul A

2006-11-30

Reactive oxygen species (ROS) play a key role in enhancing the inflammation through the activation of NF-kappaB and AP-1 transcription factors, and nuclear histone acetylation and deacetylation in various inflammatory diseases. Such undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin (diferuloylmethane, a principal component of turmeric) and resveratrol (a flavonoid found in red wine). The phenolic compounds in fruits, vegetables, tea and wine are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate NF-kappaB activation, chromatin structure, glutathione biosynthesis, nuclear redox factor (Nrf2) activation, scavenge effect of ROS directly or via glutathione peroxidase activity and as a consequence regulate inflammatory genes in macrophages and lung epithelial cells. However, recent data suggest that dietary polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. The effects of polyphenols however, have been reported to be more pronounced in vitro using high concentrations which are not physiological in vivo. This commentary discusses the recent data on dietary polyphenols in the control of signaling and inflammation particularly during oxidative stress, their metabolism and bioavailability.

Processing of CXCL12 impedes the recruitment of endothelial progenitor cells in diabetic wound healing.

PubMed

Feng, Guang; Hao, Daifeng; Chai, Jiake

2014-11-01

High blood sugar levels result in defective wound healing processes in diabetic patients. Endothelial progenitor cells (EPCs) play an important role in vasculogenesis, and thereby contribute to reconstitution of the microcirculation and healing. This study aimed to determine the possible mechanism by which the numbers of circulating EPCs are regulated in response to tissue wounding. In the streptozotocin-induced diabetic mouse model, we found that phagocytes activated by local inflammatory cytokines in the wound interfere with the mobilization and recruitment of EPCs to the lesion area. Specifically, the activated macrophages inactivate CXCL12, the major chemokine for EPC recruitment, via matrix metalloproteinases (MMPs), and thereby prevent local chemotaxis and subsequent homing of EPCs to the wound. The wound healing process is delayed by local administration of inflammatory cytokines, and its rate is increased by MMP inhibitors. This study indicates that local inhibition of MMPs is beneficial for regeneration of damaged vessels, and may explain poor wound healing in diabetic patients, thus demonstrating its potential utility as a local treatment therapy to promote diabetic wound healing. © 2014 FEBS.

Microarray-based determination of anti-inflammatory genes targeted by 6-(methylsulfinyl)hexyl isothiocyanate in macrophages.

PubMed

Chen, Jihua; Uto, Takuhiro; Tanigawa, Shunsuke; Yamada-Kato, Tomeo; Fujii, Makoto; Hou, DE-Xing

2010-01-01

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a bioactive ingredient of wasabi [Wasabia japonica (Miq.) Matsumura], which is a popular pungent spice of Japan. To evaluate the anti-inflammatory function and underlying genes targeted by 6-MSITC, gene expression profiling through DNA microarray was performed in mouse macrophages. Among 22,050 oligonucleotides, the expression levels of 406 genes were increased by ≥3-fold in lipopolysaccharide (LPS)-activated RAW264 cells, 238 gene signals of which were attenuated by 6-MSITC (≥2-fold). Expression levels of 717 genes were decreased by ≥3-fold in LPS-activated cells, of which 336 gene signals were restored by 6-MSITC (≥2-fold). Utilizing group analysis, 206 genes affected by 6-MSITC with a ≥2-fold change were classified into 35 categories relating to biological processes (81), molecular functions (108) and signaling pathways (17). The genes were further categorized as 'defense, inflammatory response, cytokine activities and receptor activities' and some were confirmed by real-time polymerase chain reaction. Ingenuity pathway analysis further revealed that wasabi 6-MSITC regulated the relevant networks of chemokines, interleukins and interferons to exert its anti-inflammatory function.

Microarray-based determination of anti-inflammatory genes targeted by 6-(methylsulfinyl)hexyl isothiocyanate in macrophages

PubMed Central

CHEN, JIHUA; UTO, TAKUHIRO; TANIGAWA, SHUNSUKE; YAMADA-KATO, TOMEO; FUJII, MAKOTO; HOU, DE-XING

2010-01-01

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a bioactive ingredient of wasabi [Wasabia japonica (Miq.) Matsumura], which is a popular pungent spice of Japan. To evaluate the anti-inflammatory function and underlying genes targeted by 6-MSITC, gene expression profiling through DNA microarray was performed in mouse macrophages. Among 22,050 oligonucleotides, the expression levels of 406 genes were increased by ≥3-fold in lipopolysaccharide (LPS)-activated RAW264 cells, 238 gene signals of which were attenuated by 6-MSITC (≥2-fold). Expression levels of 717 genes were decreased by ≥3-fold in LPS-activated cells, of which 336 gene signals were restored by 6-MSITC (≥2-fold). Utilizing group analysis, 206 genes affected by 6-MSITC with a ≥2-fold change were classified into 35 categories relating to biological processes (81), molecular functions (108) and signaling pathways (17). The genes were further categorized as ‘defense, inflammatory response, cytokine activities and receptor activities’ and some were confirmed by real-time polymerase chain reaction. Ingenuity pathway analysis further revealed that wasabi 6-MSITC regulated the relevant networks of chemokines, interleukins and interferons to exert its anti-inflammatory function. PMID:23136589

Jumonji domain-containing protein 3 regulates the early inflammatory response epigenetically in human periodontal ligament cells.

PubMed

Wang, Puyu; Yue, Junli; Xu, Weizhe; Chen, Xi; Yi, Xiaowei; Ye, Ling; Zhang, Lan; Huang, Dingming

2018-05-30

To investigate the role of the histone 3 lysine 27 trimethylation (H3K27me3) demethylase Jumonji domain-containing protein 3 (Jmjd3) in the epigenetic regulation of the inflammatory response in human periodontal ligament cells (HPDLs). HPDLs were stimulated with lipopolysaccharide from E. coli. The expression of Jmjd3 in HPDLs was examined by quantitative real-time polymerase chain reaction (Q-PCR), Western Blot and immunofluorescent staining. Potential target genes were selected by silencing Jmjd3 and were confirmed by Chromatin Immunoprecipitation (ChIP). Q-PCR, Western Blot and immunofluorescent staining revealed that the expression of Jmjd3 was increased in inflamed HPDLs. Knockdown of Jmjd3 led to the suppression of inflammation-induced up-regulation of interleukin-6 and interleukin-12. Moreover, ChIP assays demonstrated that Jmjd3 was recruited to the promoters of interleukin-6 and interleukin-12b and this recruitment was associated with decreased levels of trimethylated histone 3 lysine 27 (H3K27). It was concluded that Jmjd3 regulated the activation of interleukin-6 and interleukin-12b in the early inflammatory response of HPDLs via demethylation of H3K27me3 at promoters. This molecular event may play an important role in the regulation of the inflammatory response in HPDLs. Copyright © 2018. Published by Elsevier Ltd.

The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

PubMed Central

van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G. J.; Eleni Ourailidou, Maria; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

2016-01-01

Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4 μM for histone acetyltransferase p300). C646 was described to regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, this pathway has been implicated in asthma and COPD. Therefore we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, here we demonstrate that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7 μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account. PMID:26718586

Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression.

PubMed

Li, Yong; Pan, Yiyuan; Gao, Lin; Lu, Guotao; Zhang, Jingzhu; Xie, Xiaochun; Tong, Zhihui; Li, Baiqiang; Li, Gang; Li, Weiqin

2018-01-22

Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 μg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1β, and interleukin (IL)-1β in pancreatic tissue was detected by Western blot and real-time PCR. Dexmedetomidine at 20 μg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 μg/kg significantly down-regulated the expression of NLRP3, pro-IL-1β, and IL-1β in pancreatic tissue, but up-regulated the expression of NET in both mouse models. Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression. Copyright © 2018 Elsevier Inc. All rights reserved.

Particulate matter triggers depressive-like response associated with modulation of inflammatory cytokine homeostasis and brain-derived neurotrophic factor signaling pathway in mice.

PubMed

Liu, Xuemei; Qian, Xin; Xing, Jing; Wang, Jinhua; Sun, Yixuan; Wang, Qin'geng; Li, Huiming

2018-04-23

Particulate matter (PM) exposure may contribute to depressive-like response in mice. However, few studies have evaluated the adaptive impacts of long-term PM exposure on depressive-like response associated with systemic inflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. We studied the association among depressive-like behaviors, mRNA levels of pro- and anti-inflammatory cytokines, and the expression of BDNF signaling pathway in mice by long-term PM exposure. C57BL/6 male mice were exposed to ambient air alongside control mice breathing air filtered through a high-efficiency air PM (HEPA) filter. Depressive-like behaviors were assessed together with pro-inflammatory, anti-inflammatory cytokine mRNA levels and the modulation of BDNF pathway in hippocampus and olfactory-bulb of mice exposed to PM for 4, 8, and 12 weeks. Exposure to HEPA filtered air for 4 weeks may exert antidepressant like effects in mice. Pro-inflammatory cytokines were up-regulated while the expression of BDNF, its high-affinity receptor tropomyosin-related kinase B (TrkB), and the transcription factor cAMP-response-element binding protein (CREB) were down-regulated in ambient air mice. However, after 8 weeks, there was no significant difference in the rate of depressive-like behaviors between the two groups. After 12 weeks, mice exposed to ambient air again had a higher rate of depressive-like behaviors, significant up-regulation of pro-inflammatory cytokines, down-regulation of interleukin-10 (IL-10), BDNF, TrkB, and CREB than HEPA mice. Ultrafine PM in brain tissues of mice exposed to ambient air was observed. Our results suggest continuous high-level PM exposure alters the depressive-like response in mice and induces a damage-repair-imbalance reaction.

Glial Scar Borders Are Formed by Newly Proliferated, Elongated Astrocytes That Interact to Corral Inflammatory and Fibrotic Cells via STAT3-Dependent Mechanisms after Spinal Cord Injury

PubMed Central

Anderson, Mark A.; Song, Bingbing; Levine, Jaclynn; Fernandez, Ana; Gray-Thompson, Zachary; Ao, Yan

2013-01-01

Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons. PMID:23904622

Role of tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and associated proteins in coronary artery disease and cardiac events.

PubMed

Chemaly, Melody; McGilligan, Victoria; Gibson, Mark; Clauss, Matthias; Watterson, Steven; Alexander, H Denis; Bjourson, Anthony John; Peace, Aaron

2017-12-01

Tumour necrosis factor alpha converting enzyme (TACE/ADAM17) is a member of the A disintegrin and metalloproteinase (ADAM) family of ectodomain shedding proteinases. It regulates many inflammatory processes by cleaving several transmembrane proteins, including tumour necrosis factor alpha (TNFα) and its receptors tumour necrosis factor alpha receptor 1 and tumour necrosis factor alpha receptor 2. There is evidence that TACE is involved in several inflammatory diseases, such as ischaemia, heart failure, arthritis, atherosclerosis, diabetes and cancer as well as neurological and immune diseases. This review summarizes the latest discoveries regarding the mechanism of action and regulation of TACE. It also focuses on the role of TACE in atherosclerosis and coronary artery disease (CAD), highlighting clinical studies that have investigated its expression and protein activity. The multitude of substrates cleaved by TACE make this enzyme an attractive target for therapy and a candidate for biomarker research and development in CAD. Crown Copyright © 2017. Published by Elsevier Masson SAS. All rights reserved.

Neuromedin U: physiology, pharmacology and therapeutic potential.

PubMed

Budhiraja, S; Chugh, A

2009-04-01

Neuromedin U (NmU), a multifunctional neuropeptide, belongs to a family of neuropeptides, the neuromedins. It is ubiquitously distributed with highest levels found in the gastrointestinal tract and pituitary. The conservation of structural elements of NmU across species, the widespread distribution of NmU and its receptors throughout the body point to a fundamental role in key physiological processes. Two G protein coupled receptors for NmU have been cloned NmU R1 and NmU R2. NmU R1 is expressed pre-dominantly in the periphery especially the gastrointestinal tract whereas NmU R2 is expressed pre-dominantly in the central nervous system. Current evidence suggests a role of NmU in pain, in regulation of feeding and energy homeostasis, stress, cancer, immune mediated inflammatory diseases like asthma, inflammatory diseases, maintaining the biological clock, in the regulation of smooth muscle contraction in the gastrointestinal and genitourinary tract, and in the control of blood flow and blood pressure. With the development of drugs selectively acting on receptors and knockout animal models, exact pathophysiological roles of NmU will become clearer.

Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways.

PubMed

Hwang, Hwan-Jin; Jung, Tae Woo; Hong, Ho Cheol; Choi, Hae Yoon; Seo, Ji-A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

2013-01-01

Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis.

Neuroendocrine Factors in the Regulation of Inflammation: Excessive Adiposity and Calorie Restriction

PubMed Central

Fontana, Luigi

2009-01-01

Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of C-reactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR. PMID:18502597

Probiotic Lactobacillus-induced improvement in murine chronic inflammatory bowel disease is associated with the down-regulation of pro-inflammatory cytokines in lamina propria mononuclear cells

PubMed Central

Matsumoto, S; Hara, T; Hori, T; Mitsuyama, K; Nagaoka, M; Tomiyasu, N; Suzuki, A; Sata, M

2005-01-01

IL-6/STAT-3 signals play key roles in inflammatory bowel disease (IBD). It is known that Lactobacillus casei strain Shirota (LcS) improves inflammatory disorders. This study aimed to elucidate the effect of LcS on murine chronic IBD and to clarify the mechanism. We focused the inhibitory effect of LcS on the production of IL-6 in lipopolysaccharide (LPS)-stimulated large intestinal lamina propria mononuclear cells (LI-LPMC) isolated from mice with chronic colitis and in RAW264·7 cells in vitro. We also determined in vivo the effect of LcS on murine chronic IBD models induced with dextran sodium sulphate and SAMP1/Yit mice. Finally, we examined the cellular determinants of LcS for the down-regulation of IL-6 secretion by LI-LPMC, RAW264·7 cells and peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC). LcS, but not other strains of Lactobacillus, inhibited the production of IL-6 in LPS-stimulated LI-LPMC and RAW264·7 cells, down-regulating the nuclear translocation of NF-κB. The LcS-diet-improved murine chronic colitis is associated with the reduction of IL-6 synthesis by LI-LPMC. LcS also improved chronic ileitis in SAMP1/Yit mice. The release of IL-6 in vitro in LPS-stimulated LI-LPMC, RAW 264·7 cells and UC-PBMC was inhibited by a polysaccharide-peptidoglycan complex (PSPG) derived from LcS. This probiotic-induced improvement in murine chronic inflammatory bowel disease is associated with the down-regulation of pro-inflammatory cytokines such as IL-6 and IFN-γ production in LPMC. Therefore, LcS may be a useful probiotic for the treatment of human inflammatory bowel disease. PMID:15932502

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation.

PubMed

Xu, Xiao-Min; Zhang, Hong-Jie

2016-02-21

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract, and includes two major phenotypes: ulcerative colitis and Crohn's disease. The pathogenesis of IBD is not fully understood as of yet. It is believed that IBD results from complicated interactions between environmental factors, genetic predisposition, and immune disorders. miRNAs are a class of small non-coding RNAs that can regulate gene expression by targeting the 3'-untranslated region of specific mRNAs for degradation or translational inhibition. miRNAs are considered to play crucial regulatory roles in many biologic processes, such as immune cellular differentiation, proliferation, and apoptosis, and maintenance of immune homeostasis. Recently, aberrant expression of miRNAs was revealed to play an important role in autoimmune diseases, including IBD. In this review, we discuss the current understanding of how miRNAs regulate autoimmunity and inflammation by affecting the differentiation, maturation, and function of various immune cells. In particular, we focus on describing specific miRNA expression profiles in tissues and peripheral blood that may be associated with the pathogenesis of IBD. In addition, we summarize the opportunities for utilizing miRNAs as new biomarkers and as potential therapeutic targets in IBD.

The metastasis suppressor RARRES3 as an endogenous inhibitor of the immunoproteasome expression in breast cancer cells

NASA Astrophysics Data System (ADS)

Anderson, Alison M.; Kalimutho, Murugan; Harten, Sarah; Nanayakkara, Devathri M.; Khanna, Kum Kum; Ragan, Mark A.

2017-01-01

In breast cancer metastasis, the dynamic continuum involving pro- and anti-inflammatory regulators can become compromised. Over 600 genes have been implicated in metastasis to bone, lung or brain but how these genes might contribute to perturbation of immune function is poorly understood. To gain insight, we adopted a gene co-expression network approach that draws on the functional parallels between naturally occurring bone marrow-derived mesenchymal stem cells (BM-MSCs) and cancer stem cells (CSCs). Our network analyses indicate a key role for metastasis suppressor RARRES3, including potential to regulate the immunoproteasome (IP), a specialized proteasome induced under inflammatory conditions. Knockdown of RARRES3 in near-normal mammary epithelial and breast cancer cell lines increases overall transcript and protein levels of the IP subunits, but not of their constitutively expressed counterparts. RARRES3 mRNA expression is controlled by interferon regulatory factor IRF1, an inducer of the IP, and is sensitive to depletion of the retinoid-related receptor RORA that regulates various physiological processes including immunity through modulation of gene expression. Collectively, these findings identify a novel regulatory role for RARRES3 as an endogenous inhibitor of IP expression, and contribute to our evolving understanding of potential pathways underlying breast cancer driven immune modulation.

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome.

PubMed

Neudecker, Viola; Haneklaus, Moritz; Jensen, Owen; Khailova, Ludmila; Masterson, Joanne C; Tye, Hazel; Biette, Kathryn; Jedlicka, Paul; Brodsky, Kelley S; Gerich, Mark E; Mack, Matthias; Robertson, Avril A B; Cooper, Matthew A; Furuta, Glenn T; Dinarello, Charles A; O'Neill, Luke A; Eltzschig, Holger K; Masters, Seth L; McNamee, Eóin N

2017-06-05

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223 -/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2 + inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3' untranslated region, phenocopied the characteristics of miR-223 -/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation. © 2017 Neudecker et al.

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

PubMed Central

Khailova, Ludmila; Tye, Hazel; Jedlicka, Paul; Gerich, Mark E.; Mack, Matthias; Robertson, Avril A.B.; Dinarello, Charles A.; O’Neill, Luke A.; Eltzschig, Holger K.

2017-01-01

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation. PMID:28487310

Regulation of NF-κB-Induced Inflammatory Signaling by Lipid Peroxidation-Derived Aldehydes

PubMed Central

Yadav, Umesh C. S.; Ramana, Kota V.

2013-01-01

Oxidative stress plays a critical role in the pathophysiology of a wide range of diseases including cancer. This view has broadened significantly with the recent discoveries that reactive oxygen species initiated lipid peroxidation leads to the formation of potentially toxic lipid aldehyde species such as 4-hydroxy-trans-2-nonenal (HNE), acrolein, and malondialdehyde which activate various signaling intermediates that regulate cellular activity and dysfunction via a process called redox signaling. The lipid aldehyde species formed during synchronized enzymatic pathways result in the posttranslational modification of proteins and DNA leading to cytotoxicity and genotoxicty. Among the lipid aldehyde species, HNE has been widely accepted as a most toxic and abundant lipid aldehyde generated during lipid peroxidation. HNE and its glutathione conjugates have been shown to regulate redox-sensitive transcription factors such as NF-κB and AP-1 via signaling through various protein kinase cascades. Activation of redox-sensitive transcription factors and their nuclear localization leads to transcriptional induction of several genes responsible for cell survival, differentiation, and death. In this review, we describe the mechanisms by which the lipid aldehydes transduce activation of NF-κB signaling pathways that may help to develop therapeutic strategies for the prevention of a number of inflammatory diseases. PMID:23710287

Endogenous hydrogen sulfide regulates histone demethylase JMJD3-mediated inflammatory response in LPS-stimulated macrophages and in a mouse model of LPS-induced septic shock.

PubMed

Liu, Siyu; Wang, Xiling; Pan, Lilong; Wu, Weijun; Yang, Di; Qin, Ming; Jia, Wanwan; Xiao, Chenxi; Long, Fen; Ge, Junbo; Liu, Xinhua; Zhu, YiZhun

2018-03-01

Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock. Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H 2 S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models. LPS stimulation also enhanced the activation of JMJD3 and decreased H3K27me3 levels. JMJD3 knockdown upregulated H3K27me3 levels and attenuated the LPS-mediated inflammatory response. CSE knockout amplified the inflammatory cascade by increasing JMJD3 expression in septic mice. Similarly, enhanced production of inflammatory mediators by macrophages was mitigated by CSE overexpression via inhibition of JMJD3 expression. This is the first report indicating that inflammation enhanced CSE/H 2 S system biosynthesis, that in turn attenuated the LPS-triggered inflammatory response by regulating JMJD3 expression. Thus, the CSE/H 2 S system represents an epigenetic-based modification mechanism to prevent uncontrolled inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of Nlrp3 inflammasome by dietary metabolites

PubMed Central

Camell, Christina; Goldberg, Emily; Dixit, Vishwa Deep

2015-01-01

The bidirectional communication between innate immune cells and energy metabolism is now widely appreciated to regulate homeostasis as well as chronic diseases that emerge from dysregulated inflammation. Macronutrients-derived from diet or endogenous pathways that generate and divert metabolites into energetic or biosynthetic pathways-regulate the initiation, duration and cessation of the inflammatory response. The NLRP3 inflammasome is an important innate sensor of structurally diverse metabolic damage-associated molecular patterns (DAMPs) that has been implicated in a wide range of inflammatory disorders associated with caloric excess, adiposity and aging. Understanding the regulators of immune-metabolic interactions and their contribution towards chronic disease mechanisms, therefore, has the potential to reduce disease pathology, improve quality of life in elderly and promote the extension of healthspan. Just as specialized subsets of immune cells dampen inflammation through the production of negative regulatory cytokines; specific immunoregulatory metabolites can deactivate inflammasome-mediated immune activation. Here, we highlight the role of energy substrates, alternative fuels and metabolic DAMPs in the regulation of the NLRP3 inflammasome and discuss potential dietary interventions that may impact sterile inflammatory disease. PMID:26776831

p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes.

PubMed

Yu, Xiaoling; Jin, Dan; Yu, An; Sun, Jun; Chen, Xiaodong; Yang, Zaiqing

2016-09-01

DEPTOR, a novel endogenous inhibitor of mTOR, plays an important role in regulating the inflammatory response in vascular endothelial cells (ECs) and in mouse skeletal muscle. However, the regulatory mechanism of DEPTOR transcription and its effects on liver inflammation are unknown presently. Here we reported the role of DEPTOR in regulating inflammatory response in mouse liver-derived Hepa1-6 cells and in a mouse model with LPS-induced hepatic inflammation. The results revealed that DEPTOR over-expression in Hepa1-6 liver cells increased the mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). Contrasting results were observed in Hepa1-6 cells with DEPTOR interference. Treatment Hepa1-6 cells with rapamycin, a specific inhibitor of mTORC1, increased MCP-1 mRNA, but have no significant effect on IL-6 mRNA. DEPTOR expression was down-regulated in Hepa1-6 cells with the treatment of inflammatory stimuli LPS or the over-expression of p65/NF-κB, a key inflammatory transcription factor. NF-κB antagonist (PDTC) and inhibitor (IκBα) blocked the effect of LPS on DEPTOR expression. The study in vivo showed that DEPTOR mRNA and protein were significantly reduced in a mouse model with LPS-induced hepatic inflammation, which was accompanied by a concurrent activation of the mTOR signaling pathway. Further, the transcriptional regulation of DEPTOR was explored, which revealed that DEPTOR promoter activity was significantly down-regulated by NF-κB. The progressive deletions and mutations demonstrated that the NF-κB binding motif situated at -145/-127 region is an essential component required for the DEPTOR promoter activity. Chromatin immunoprecipitation (ChIP) assays determined that p65 can directly interact with the DEPTOR promoter DNA. Those results indicate DEPTOR regulates liver inflammation at least partially via mTORC1 pathway, and is down-regulated by LPS through p65. Copyright © 2016 Elsevier B.V. All rights reserved.

Inflammatory, metabolic, and genetic mechanisms of vascular calcification

PubMed Central

Demer, Linda L.; Tintut, Yin

2014-01-01

This review centers on updating the active research area of vascular calcification. This pathology underlies substantial cardiovascular morbidity and mortality, through adverse mechanical effects on vascular compliance, vasomotion, and, most likely, plaque stability. Biomineralization is a complex, regulated process occurring widely throughout nature. Decades ago, its presence in the vasculature was considered a mere curiosity and an unregulated, “dystrophic” process that does not involve biological mechanisms. While it remains controversial whether the process has any adaptive value or past evolutionary advantage, substantial advances have been made in understanding the biological mechanisms driving the process. Different types of calcific vasculopathy, such as inflammatory vs. metabolic, have parallel mechanisms in skeletal bone calcification, such as intramembranous and endochondral ossification. Recent work has identified important regulatory roles for inflammation, oxidized lipids, elastin, alkaline phosphatase, osteoprogenitor cells, matrix gamma-carboxyglutamic acid protein (MGP), transglutaminase, osteoclastic regulatory factors, phosphate regulatory hormones and receptors, apoptosis, prelamin A, autophagy, and microvesicles or microparticles similar to the matrix vesicles of skeletal bone. Recent work has uncovered fascinating interactions between MGP, vitamin K, warfarin and transport proteins. And, lastly, recent breakthroughs in inherited forms of calcific vasculopathy, have identified the genes responsible as well as an unexpected overlap of phenotypes. PMID:24665125

Analysis of hepatic transcript profile and plasma lipid profile in early lactating dairy cows fed grape seed and grape marc meal extract.

PubMed

Gessner, Denise K; Winkler, Anne; Koch, Christian; Dusel, Georg; Liebisch, Gerhard; Ringseis, Robert; Eder, Klaus

2017-03-23

It was recently reported that dairy cows fed a polyphenol-rich grape seed and grape marc meal extract (GSGME) during the transition period had an increased milk yield, but the underlying reasons remained unclear. As polyphenols exert a broad spectrum of metabolic effects, we hypothesized that feeding of GSGME influences metabolic pathways in the liver which could account for the positive effects of GSGME in dairy cows. In order to identify these pathways, we performed genome-wide transcript profiling in the liver and lipid profiling in plasma of dairy cows fed GSGME during the transition period at 1 week postpartum. Transcriptomic analysis of the liver revealed 207 differentially expressed transcripts, from which 156 were up- and 51 were down-regulated, between cows fed GSGME and control cows. Gene set enrichment analysis of the 155 up-regulated mRNAs showed that the most enriched gene ontology (GO) biological process terms were dealing with cell cycle regulation and the most enriched Kyoto Encyclopedia of Genes and Genomes pathways were p53 signaling and cell cycle. Functional analysis of the 43 down-regulated mRNAs revealed that a great part of these genes are involved in endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and inflammatory processes. Accordingly, protein folding, response to unfolded protein, unfolded protein binding, chemokine activity and heat shock protein binding were identified as one of the most enriched GO biological process and molecular function terms assigned to the down-regulated genes. In line with the transcriptomics data the plasma concentrations of the acute phase proteins serum amyloid A (SAA) and haptoglobin were reduced in cows fed GSGME compared to control cows. Lipidomic analysis of plasma revealed no differences in the concentrations of individual species of major and minor lipid classes between cows fed GSGME and control cows. Analysis of hepatic transcript profile in cows fed GSGME during the transition period at 1 week postpartum indicates that polyphenol-rich feed components are able to inhibit ER stress-induced UPR and inflammatory processes, both of which are considered to contribute to liver-associated diseases and to impair milk performance in dairy cows, in the liver of dairy cows during early lactation.

Anti-inflammatory effects of flavonoids in neurodegenerative disorders.

PubMed

Spagnuolo, Carmela; Moccia, Stefania; Russo, Gian Luigi

2018-06-10

Neuroinflammation is one of the main mechanisms involved in the progression of several neurodegenerative diseases, such as Parkinson, Alzheimer, multiple sclerosis, amyotrophic lateral sclerosis and others. The activation of microglia is the main feature of neuroinflammation, promoting the release of pro-inflammatory cytokines and resulting in the progressive neuronal cell death. Natural compounds, such as flavonoids, possess neuroprotective potential probably related to their ability to modulate the inflammatory responses involved in neurodegenerative diseases. In fact, pure flavonoids (e.g., quercetin, genistein, hesperetin, epigallocatechin-3-gallate) or enriched-extracts, can reduce the expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2), down-regulate inflammatory markers and prevent neural damage. This anti-inflammatory activity is primarily related to the regulation of microglial cells, mediated by their effects on MAPKs and NF-κB signalling pathways, as demonstrated by in vivo and in vitro data. The present work reviews the role of inflammation in neurodegenerative diseases, highlighting the potential therapeutic effects of flavonoids as a promising approach to develop innovative neuroprotective strategy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Gene expression profiling following NRF2 and KEAP1 siRNA knockdown in human lung fibroblasts identifies CCL11/Eotaxin-1 as a novel NRF2 regulated gene

PubMed Central

2012-01-01

Background Oxidative Stress contributes to the pathogenesis of many diseases. The NRF2/KEAP1 axis is a key transcriptional regulator of the anti-oxidant response in cells. Nrf2 knockout mice have implicated this pathway in regulating inflammatory airway diseases such as asthma and COPD. To better understand the role the NRF2 pathway has on respiratory disease we have taken a novel approach to define NRF2 dependent gene expression in a relevant lung system. Methods Normal human lung fibroblasts were transfected with siRNA specific for NRF2 or KEAP1. Gene expression changes were measured at 30 and 48 hours using a custom Affymetrix Gene array. Changes in Eotaxin-1 gene expression and protein secretion were further measured under various inflammatory conditions with siRNAs and pharmacological tools. Results An anti-correlated gene set (inversely regulated by NRF2 and KEAP1 RNAi) that reflects specific NRF2 regulated genes was identified. Gene annotations show that NRF2-mediated oxidative stress response is the most significantly regulated pathway, followed by heme metabolism, metabolism of xenobiotics by Cytochrome P450 and O-glycan biosynthesis. Unexpectedly the key eosinophil chemokine Eotaxin-1/CCL11 was found to be up-regulated when NRF2 was inhibited and down-regulated when KEAP1 was inhibited. This transcriptional regulation leads to modulation of Eotaxin-1 secretion from human lung fibroblasts under basal and inflammatory conditions, and is specific to Eotaxin-1 as NRF2 or KEAP1 knockdown had no effect on the secretion of a set of other chemokines and cytokines. Furthermore, the known NRF2 small molecule activators CDDO and Sulphoraphane can also dose dependently inhibit Eotaxin-1 release from human lung fibroblasts. Conclusions These data uncover a previously unknown role for NRF2 in regulating Eotaxin-1 expression and further the mechanistic understanding of this pathway in modulating inflammatory lung disease. PMID:23061798

Gene expression profiling following NRF2 and KEAP1 siRNA knockdown in human lung fibroblasts identifies CCL11/Eotaxin-1 as a novel NRF2 regulated gene.

PubMed

Fourtounis, Jimmy; Wang, I-Ming; Mathieu, Marie-Claude; Claveau, David; Loo, Tenneille; Jackson, Aimee L; Peters, Mette A; Therien, Alex G; Boie, Yves; Crackower, Michael A

2012-10-12

Oxidative Stress contributes to the pathogenesis of many diseases. The NRF2/KEAP1 axis is a key transcriptional regulator of the anti-oxidant response in cells. Nrf2 knockout mice have implicated this pathway in regulating inflammatory airway diseases such as asthma and COPD. To better understand the role the NRF2 pathway has on respiratory disease we have taken a novel approach to define NRF2 dependent gene expression in a relevant lung system. Normal human lung fibroblasts were transfected with siRNA specific for NRF2 or KEAP1. Gene expression changes were measured at 30 and 48 hours using a custom Affymetrix Gene array. Changes in Eotaxin-1 gene expression and protein secretion were further measured under various inflammatory conditions with siRNAs and pharmacological tools. An anti-correlated gene set (inversely regulated by NRF2 and KEAP1 RNAi) that reflects specific NRF2 regulated genes was identified. Gene annotations show that NRF2-mediated oxidative stress response is the most significantly regulated pathway, followed by heme metabolism, metabolism of xenobiotics by Cytochrome P450 and O-glycan biosynthesis. Unexpectedly the key eosinophil chemokine Eotaxin-1/CCL11 was found to be up-regulated when NRF2 was inhibited and down-regulated when KEAP1 was inhibited. This transcriptional regulation leads to modulation of Eotaxin-1 secretion from human lung fibroblasts under basal and inflammatory conditions, and is specific to Eotaxin-1 as NRF2 or KEAP1 knockdown had no effect on the secretion of a set of other chemokines and cytokines. Furthermore, the known NRF2 small molecule activators CDDO and Sulphoraphane can also dose dependently inhibit Eotaxin-1 release from human lung fibroblasts. These data uncover a previously unknown role for NRF2 in regulating Eotaxin-1 expression and further the mechanistic understanding of this pathway in modulating inflammatory lung disease.

Resolution of inflammation: state of the art, definitions and terms

PubMed Central

Serhan, Charles N.; Brain, Sue D.; Buckley, Christopher D.; Gilroy, Derek W.; Haslett, Christopher; O’Neill, Luke A. J.; Perretti, Mauro; Rossi, Adriano G.; Wallace, John L.

2011-01-01

A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution. PMID:17267386

Immunology Comes Full Circle in Melanoma While Specific Immunity Is Unleashed to Eliminate Metastatic Disease, Inflammatory Products of Innate Immunity Promote Resistance.

PubMed

Grimm, Elizabeth A

2016-01-01

Melanoma and many other cancers often express cells and molecular features of inflammation. Intrinsic to melanoma is the expression of a continuous cycle of cytokines and oxidative stress markers. The oxidative stress of inflammation is proposed to drive a metastatic process, not only of DNA adducts and crosslinks, but also of posttranslational oxidative modifications to lipids and proteins that we argue support growth and survival. Fortunately, numerous antioxidant agents are available clinically and we further propose that the pharmacological attenuation of these inflammatory processes, particularly the reactive nitrogen species, will restore the cancer cells to an apoptosis-permissive and growth-inhibitory state. Experimental model data using a small-molecule arginine antagonist that prevents enzymatic production of nitric oxide supports this view directly. I propose that the recognition, measurement, and regulation of such carcinogenic inflammation be considered as part of the approach to the treatment of cancer.

By Capturing Inflammatory Lipids Released from Dying Cells, the Receptor CD14 Induces Inflammasome-Dependent Phagocyte Hyperactivation.

PubMed

Zanoni, Ivan; Tan, Yunhao; Di Gioia, Marco; Springstead, James R; Kagan, Jonathan C

2017-10-17

A heterogeneous mixture of lipids called oxPAPC, derived from dying cells, can hyperactivate dendritic cells (DCs) but not macrophages. Hyperactive DCs are defined by their ability to release interleukin-1 (IL-1) while maintaining cell viability, endowing these cells with potent aptitude to stimulate adaptive immunity. Herein, we found that the bacterial lipopolysaccharide receptor CD14 captured extracellular oxPAPC and delivered these lipids into the cell to promote inflammasome-dependent DC hyperactivation. Notably, we identified two specific components within the oxPAPC mixture that hyperactivated macrophages, allowing these cells to release IL-1 for several days, by a CD14-dependent process. In murine models of sepsis, conditions that promoted cell hyperactivation resulted in inflammation but not lethality. Thus, multiple phagocytes are capable of hyperactivation in response to oxPAPC, with CD14 acting as the earliest regulator in this process, serving to capture and transport these lipids to promote inflammatory cell fate decisions. Copyright © 2017 Elsevier Inc. All rights reserved.

Inflammatory parameters in Caco-2 cells: effect of stimuli nature, concentration, combination and cell differentiation.

PubMed

Van De Walle, Jacqueline; Hendrickx, Aurélie; Romier, Béatrice; Larondelle, Yvan; Schneider, Yves-Jacques

2010-08-01

Enterocytes regulate gut maintenance and defence by secreting and responding to inflammatory mediators and by modulating the intestinal epithelial permeability. In order to develop an in vitro model of the acute phase of intestinal inflammation, Caco-2 cells were exposed to the inflammatory mediators IL-1beta, TNF-alpha, IFN-gamma and LPS, and the importance of several experimental parameters, i.e. cell differentiation, stimulus nature, concentration and combination on the inflammatory response was assessed by measuring the production of IL-6, IL-8, PGE-2 and NO and by evaluating the monolayer permeability. A maximal increase in IL-8, IL-6 and PGE-2 production and monolayer permeability was observed when using the cytokines simultaneously at their highest level, but this relied mainly on IL-1beta. The effects of TNF-alpha on IL-8 and IL-6 or NO production were stronger upon combination with IL-1beta or IFN-gamma, respectively, whereas cells were unaffected by the presence of LPS. Although NO production, induced by IFN-gamma-containing combinations, was observed only in differentiated cells, general inflammatory response was higher in proliferating cells. The use of a mixture of IL-1beta, TNF-alpha and IFN-gamma thus accurately mimics intestinal inflammatory processes, but cell differentiation and stimuli combination are important parameters to take into account for in vitro studies on intestinal inflammation. Copyright (c) 2010. Published by Elsevier Ltd.

Specific depletion of Ly6C(hi) inflammatory monocytes prevents immunopathology in experimental cerebral malaria.

PubMed

Schumak, Beatrix; Klocke, Katrin; Kuepper, Janina M; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

2015-01-01

Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6C(hi) inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C(hi) inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C(hi) inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes.

Specific Depletion of Ly6Chi Inflammatory Monocytes Prevents Immunopathology in Experimental Cerebral Malaria

PubMed Central

Kuepper, Janina M.; Biswas, Aindrila; Djie-Maletz, Andrea; Limmer, Andreas; van Rooijen, Nico; Mack, Matthias; Hoerauf, Achim; Dunay, Ildiko Rita

2015-01-01

Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6Chi inflammatory monocytes (by anti-CCR2), Ly6G+ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6Chi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ+CD8+ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6Chi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C+ monocytes in ECM inflammatory processes. PMID:25884830

Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization.

PubMed

Lu, Hong; Wu, Lianfeng; Liu, Leping; Ruan, Qingqing; Zhang, Xing; Hong, Weilong; Wu, Shijia; Jin, Guihua; Bai, Yongheng

2018-05-15

Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Further study revealed that quercetin inhibited the infiltration of CD68+ macrophages in renal interstitium. Moreover, the decrease in levels of iNOS and IL-12, as well as the proportion of F4/80+/CD11b+/CD86+ macrophages, indicated quercetin-mediated inhibition of M1 macrophage polarization in the injured kidneys. In cultured macrophages, lipopolysaccharide-induced inflammatory polarization was suppressed by quercetin treatment, resulting in the reduction of the release of inflammatory factors. Notably, quercetin-induced inhibitory effects on inflammatory macrophage polarization were associated with down-regulated activities of NF-κB p65 and IRF5, and thus led to the inactivation of upstream signaling TLR4/Myd88. Interestingly, quercetin also inhibited the polarization of F4/80+/CD11b+/CD206+ M2 macrophages, and reduced excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing the TGF-β1/Smad2/3 signaling. Thus, quercetin ameliorates kidney injury via modulating macrophage polarization, and may have therapeutic potential for patients with kidney injury. Copyright © 2018 Elsevier Inc. All rights reserved.

New insights into the human body iron metabolism analyzed by a Petri net based approach.

PubMed

Sackmann, Andrea; Formanowicz, Dorota; Formanowicz, Piotr; Blazewicz, Jacek

2009-04-01

Iron homeostasis is one of the most important biochemical processes in the human body. Despite this fact, the process is not fully understood and until recently only rough descriptions of parts of the process could be found in the literature. Here, an extension of the recently published formal model of the main part of the process is presented. This extension consists in including all known mechanisms of hepcidin regulation. Hepcidin is a hormone synthesized in the liver which is mainly responsible for an inhibition of iron absorption in the small intestine during an inflammatory process. The model is expressed in the language of Petri net theory which allows for its relatively easy analysis and simulation.

Could Notch signaling pathway be a potential therapeutic option in renal diseases?

PubMed

Marquez-Exposito, Laura; Cantero-Navarro, Elena; Lavoz, Carolina; Fierro-Fernández, Marta; Poveda, Jonay; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Morgado-Pascual, José Luis; Orejudo, Macarena; Mezzano, Sergio; Ruiz-Ortega, Marta

2018-02-10

Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Multimodal Regulation of Circadian Glucocorticoid Rhythm by Central and Adrenal Clocks.

PubMed

Son, Gi Hoon; Cha, Hyo Kyeong; Chung, Sooyoung; Kim, Kyungjin

2018-05-01

Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases.

Multimodal Regulation of Circadian Glucocorticoid Rhythm by Central and Adrenal Clocks

PubMed Central

Son, Gi Hoon; Cha, Hyo Kyeong; Chung, Sooyoung; Kim, Kyungjin

2018-01-01

Abstract Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic–pituitary–adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases. PMID:29713692

Involvement of the nitric oxide in melatonin-mediated protection against injury.

PubMed

Fan, Wenguo; He, Yifan; Guan, Xiaoyan; Gu, Wenzhen; Wu, Zhi; Zhu, Xiao; Huang, Fang; He, Hongwen

2018-05-01

Melatonin is a hormone mainly synthesized by the pineal gland in vertebrates and known well as an endogenous regulator of circadian and seasonal rhythms. It has been demonstrated that melatonin is involved in many physiological and pathophysiological processes showing antioxidant, anti-apoptotic and anti-inflammatory properties. Nitric oxide (NO) is a free radical gas in the biological system, which is produced by nitric oxide synthase (NOS) family. NO acts as a biological mediator and plays important roles in different systems in humans. The NO/NOS system exerts a broad spectrum of signaling functions. Accumulating evidence has clearly revealed that melatonin regulates NO/NOS system through multiple mechanisms that may influence physiological and pathophysiological processes. This article reviews the latest evidence for the effects of melatonin on NO/NOS regulation in different organs and disease conditions, the potential cellular mechanisms by which melatonin is involved in organ protection are discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Noncoding RNAs and chronic inflammation: Micro‐managing the fire within

PubMed Central

Alexander, Margaret

2015-01-01

Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age‐associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. Copyright Line: © 2015 The Authors BioEssays Published by Wiley‐VCH Verlag GmbH & Co. KGaA. PMID:26249326

Evaluation of epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes and concerns on osteoblasts.

PubMed

Chu, Chenyu; Deng, Jia; Xiang, Lin; Wu, Yingying; Wei, Xiawei; Qu, Yili; Man, Yi

2016-10-01

Collagen membranes have ideal biological and mechanical properties for supporting infiltration and proliferation of osteoblasts and play a vital role in guided bone regeneration (GBR). However, pure collagen can lead to inflammation, resulting in progressive bone resorption. Therefore, a method for regulating the level of inflammatory cytokines at surgical sites is paramount for the healing process. Epigallocatechin-3-gallate (EGCG) is a component extracted from green tea with numerous biological activities including an anti-inflammatory effect. Herein, we present a novel cross-linked collagen membrane containing different concentrations of EGCG (0.0064%, 0.064%, and 0.64%) to regulate the level of inflammatory factors secreted by pre-osteoblast cells; improve cell proliferation; and increase the tensile strength, wettability, and thermal stability of collagen membranes. Scanning electron microscope images show that the surfaces of collagen membranes became smoother and the collagen fiber diameters became larger with EGCG treatment. Measurement of the water contact angle demonstrated that introducing EGCG improved membrane wettability. Fourier transform infrared spectroscopy analyses indicated that the backbone of collagen was intact, and the thermal stability was significant improved in differential scanning calorimetry. The mechanical properties of 0.064% and 0.64% EGCG-treated collagen membranes were 1.5-fold greater than those of the control. The extent of cross-linking was significantly increased, as determined by a 2,4,6-trinitrobenzenesulfonic acid solution assay. The Cell Counting Kit-8 (CCK-8) and live/dead assays revealed that collagen membrane cross-linked by 0.0064% EGCG induced greater cell proliferation than pure collagen membranes. Additionally, real-time polymerase chain reaction and enzyme-linked immunosorbent assay results showed that EGCG significantly affected the production of inflammatory factors secreted by MC3T3-E1 cells. Taken together, our results indicate that treatment of collagen membranes with appropriate concentrations of EGCG has an anti-inflammatory effect and shows promise for GBR applications. Copyright © 2016. Published by Elsevier B.V.

AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO.

PubMed

Koch, S; Stroisch, T J; Vorac, J; Herrmann, N; Leib, N; Schnautz, S; Kirins, H; Förster, I; Weighardt, H; Bieber, T

2017-11-01

Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of patients with atopic dermatitis (AD) carry the high-affinity receptor for IgE, FcεRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes. We investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC. Epidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34 + hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR. Epidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused downregulation of FcεRI in CD34LC without affecting their maturation. AhR-mediated regulation of FcεRI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement. Our study shows that AhR activation by FICZ reduces FcεRI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor

PubMed Central

Klaver, Elsenoor J.; Kuijk, Loes M.; Lindhorst, Thisbe K.; Cummings, Richard D.; van Die, Irma

2015-01-01

Schistosomiasis is a common debilitating human parasitic disease in (sub)tropical areas, however, schistosome infections can also protect against a variety of inflammatory diseases. This has raised broad interest in the mechanisms by which Schistosoma modulate the immune system into an anti-inflammatory and regulatory state. Human dendritic cells (DCs) show many phenotypic changes upon contact with Schistosoma mansoni soluble egg antigens (SEA). We here show that oxidation of SEA glycans, but not heat-denaturation, abrogates the capacity of SEA to suppress both LPS-induced cytokine secretion and DC proliferation, indicating an important role of SEA glycans in these processes. Remarkably, interaction of SEA glycans with DCs results in a strongly increased expression of Suppressor Of Cytokine Signalling1 (SOCS1) and SH2-containing protein tyrosine Phosphatase-1 (SHP1), important negative regulators of TLR4 signalling. In addition, SEA induces the secretion of transforming growth factor β (TGF-β), and the surface expression of the costimulatory molecules Programmed Death Ligand-1 (PD-L1) and OX40 ligand (OX40L), which are known phenotypic markers for the capacity of DCs to polarize naïve T cells into Th2/Treg cell subsets. Inhibition of mannose receptor (MR)-mediated internalization of SEA into DCs by blocking with allyl α-D-mannoside or anti-MR antibodies, significantly reduced SOCS1 and SHP1 expression. In conclusion, we demonstrate that SEA glycans are essential for induction of enhanced SOCS1 and SHP1 levels in DCs via the MR. Our data provide novel mechanistic evidence for the potential of S. mansoni SEA glycans to modulate human DCs, which may contribute to the capacity of SEA to down-regulate inflammatory responses. PMID:25897665

Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor.

PubMed

Klaver, Elsenoor J; Kuijk, Loes M; Lindhorst, Thisbe K; Cummings, Richard D; van Die, Irma

2015-01-01

Schistosomiasis is a common debilitating human parasitic disease in (sub)tropical areas, however, schistosome infections can also protect against a variety of inflammatory diseases. This has raised broad interest in the mechanisms by which Schistosoma modulate the immune system into an anti-inflammatory and regulatory state. Human dendritic cells (DCs) show many phenotypic changes upon contact with Schistosoma mansoni soluble egg antigens (SEA). We here show that oxidation of SEA glycans, but not heat-denaturation, abrogates the capacity of SEA to suppress both LPS-induced cytokine secretion and DC proliferation, indicating an important role of SEA glycans in these processes. Remarkably, interaction of SEA glycans with DCs results in a strongly increased expression of Suppressor Of Cytokine Signalling1 (SOCS1) and SH2-containing protein tyrosine Phosphatase-1 (SHP1), important negative regulators of TLR4 signalling. In addition, SEA induces the secretion of transforming growth factor β (TGF-β), and the surface expression of the costimulatory molecules Programmed Death Ligand-1 (PD-L1) and OX40 ligand (OX40L), which are known phenotypic markers for the capacity of DCs to polarize naïve T cells into Th2/Treg cell subsets. Inhibition of mannose receptor (MR)-mediated internalization of SEA into DCs by blocking with allyl α-D-mannoside or anti-MR antibodies, significantly reduced SOCS1 and SHP1 expression. In conclusion, we demonstrate that SEA glycans are essential for induction of enhanced SOCS1 and SHP1 levels in DCs via the MR. Our data provide novel mechanistic evidence for the potential of S. mansoni SEA glycans to modulate human DCs, which may contribute to the capacity of SEA to down-regulate inflammatory responses.

Celecoxib prevents colitis associated colon carcinogenesis: an upregulation of apoptosis.

PubMed

Setia, Shruti; Nehru, Bimla; Sanyal, Sankar N

2014-12-01

Uncontrolled cell proliferation and suppressed apoptosis are the critical events transforming a normal cell to a cancerous one wherein the inflammatory microenvironment supports this oncogenic transformation. The process of colon carcinogenesis may be aggravated in chronic inflammatory conditions such as ulcerative colitis where non-steroidal anti-inflammatory drugs (NSAIDs) may effectively prevent the cellular and molecular events. Western blots and immunofluorescent analysis of DNA mismatch repair enzymes, cell cycle regulators and pro- and anti-apoptotic proteins were performed in dextran sulfate sodium (DSS)-induced ulcerative colitis and 1,2-dimethyl benz(a)anthracene (DMH)-induced colon cancer. Also, apoptotic studies were done in isolated colonocytes using fluorescent staining and in paraffin sections using TUNEL assay. An upregulation of cell cycle regulators: cyclin D1/cdk4 and cyclin E/cdk2 and anti-apoptotic Bcl-2, along with the suppression of DNA repair enzymes: MLH1 and MSH2; tumour suppressors: p53, p21and Rb and pro-apoptotic proteins: Bax and Bad were observed in the DSS, DMH and DSS+DMH groups. Proliferating cell nuclear antigen (PCNA) was also overexpressed in these groups. The ultimate executioner of the apoptotic pathway; caspase-3, was suppressed in these groups. Apoptotic studies in colonocytes and paraffin sections revealed suppressed apoptosis in these groups. These effects were corrected with the administration of a second generation NSAID, celecoxib along with the treatment of DSS and DMH. The chemopreventive action of celecoxib in colitis mediated colon carcinogenesis may include the regulation of DNA mismatch repair enzymes, cell cycle check points, cell proliferation and apoptosis. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Interaction of the endocrine system with inflammation: a function of energy and volume regulation

PubMed Central

2014-01-01

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases. PMID:24524669

Interaction of the endocrine system with inflammation: a function of energy and volume regulation.

PubMed

Straub, Rainer H

2014-02-13

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases.

Deacetylases and NF-κB in Redox Regulation of Cigarette Smoke induced Lung Inflammation: Implications in Pathogenesis of COPD

PubMed Central

Rajendrasozhan, Saravanan; Yang, Se-Ran; Edirisinghe, Indika; Yao, Hongwei; Adenuga, David; Rahman, Irfan

2009-01-01

Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders including chronic obstructive pulmonary disease (COPD) due to its effect on pro-inflammatory gene transcription. Cigarette smoke-mediated oxidative stress activates NF-κB-dependent transcription of pro-inflammatory mediators either through activation of inhibitor κB-α kinase (IKK) and/or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increase in chromatin modifications, such as histone acetylation leading to inflammatory gene transcription. NF-κB-dependent gene expression, at least in part, is regulated by changes in deacetylases such as histone deacetylases (HDACs) and sirtuins. Cigarette smoke and oxidants also alter the levels/activity of HDAC by post-translational modifications and in doing so further induces gene expression of pro-inflammatory mediators. In addition, cigarette smoke/oxidants can reduce glucocorticoid sensitivity by attenuating HDAC2 activity and expression, which may account for the glucocorticoid insensitivity in patients with COPD. Understanding the mechanisms of NF-κB regulation, and the balance between histone acetylation and deacetylation may lead to the development of novel therapies based on the pharmacological manipulation of IKK and deacetylases in lung inflammation and injury. PMID:18220485

Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villar-Lorenzo, Andrea, E-mail: avillar@iib.uam.es

A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25 μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) andmore » increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation. - Highlights: • Compounds 18 (C18) and 25 (C25) exert anti-inflammatory effects in macrophages. • C18 enhanced nuclear translocation of Nrf2 and increased HO1 expression. • C25 inhibited the phosphorylation of JNK, p38 and ERK, members of the MAPKs family. • C25 reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β. • C18 and C25 may be therapeutic agents for diseases linked to inflammation.« less

Cutting edge: A transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway.

PubMed

El Kasmi, Karim C; Smith, Amber M; Williams, Lynn; Neale, Geoffrey; Panopoulos, Athanasia D; Panopolous, Athanasia; Watowich, Stephanie S; Häcker, Hans; Foxwell, Brian M J; Murray, Peter J

2007-12-01

IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on proinflammatory mediator production. In this study we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3, and a helicase family corepressor, Strawberry notch homologue 2 (SBNO2), in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3 and a stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway regulated by IL-10 but not by STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 repressed NF-kappaB- but not IFN regulatory factor 7 (IRF7)-activated transcriptional reporters. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10.

Regulation of the ovarian inflammatory response at ovulation by nuclear progesterone receptor.

PubMed

Akison, Lisa K; Robertson, Sarah A; Gonzalez, Macarena B; Richards, JoAnne S; Smith, C Wayne; Russell, Darryl L; Robker, Rebecca L

2018-06-01

The nuclear progesterone receptor (PGR) transcription factor is essential for ovulation; however, the exact mechanisms by which PGR controls ovulation are not known. The aim of this study was to determine whether PGR regulates inflammatory mediators in the ovary. Ovaries from mice lacking PGR (PRKO) and heterozygous PR+/- littermates were subjected to microarray analysis of a large panel of inflammatory genes. Immune cell subsets were detected by gene expression; and neutrophils by immunohistochemistry and chemotaxis assay. PRKO ovaries exhibited dysregulated expression of vasodilator (Edn1), cytokine (Il-6, Tgfb1), adhesion receptor (Cd34), apoptotic factor (Bax) and transcription factors (Nfkb2, Socs1, Stat3). Ptgs2 was also reduced in PRKO ovaries, but mRNA and protein were not different in granulosa cells. There were reduced neutrophils in ovaries of PRKO mice at ovulation; however, chemotaxis assays showed PRKO neutrophils migrate normally and that PRKO ovarian extracts exhibit chemotactic properties in vitro. Specific inflammatory mediators are altered in the ovaries of PRKO mice indicating that progesterone regulates features of inflammation at ovulation. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anti-steatotic and anti-inflammatory roles of syringic acid in high-fat diet-induced obese mice.

PubMed

Ham, Ju Ri; Lee, Hae-In; Choi, Ra-Yeong; Sim, Mi-Ok; Seo, Kwon-Il; Lee, Mi-Kyung

2016-02-01

This study examined the effects of syringic acid (SA) on obese diet-induced hepatic dysfunction. Mice were fed high-fat diet (HFD) with or without SA (0.05%, wt/wt) for 16 weeks. SA reduced the body weight, visceral fat mass, serum levels of leptin, TNFα, IFNγ, IL-6 and MCP-1, insulin resistance, hepatic lipid content, droplets and early fibrosis, whereas it elevated the circulation of adiponectin. SA down-regulated lipogenic genes (Cidea, Pparγ, Srebp-1c, Srebp-2, Hmgcr, Fasn) and inflammatory genes (Tlr4, Myd88, NF-κB, Tnfα, Il6), whereas it up-regulated fatty acid oxidation genes (Pparα, Acsl, Cpt1, Cpt2) in the liver. SA also decreased hepatic lipogenic enzyme activities and elevated fatty acid oxidation enzyme activities relative to the HFD group. These findings suggested that dietary SA possesses anti-obesity, anti-inflammatory and anti-steatotic effects via the regulation of lipid metabolic and inflammatory genes. SA is likely to be a new natural therapeutic agent for obesity or non-alcoholic liver disease.

The recent progress of the mechanism and regulation of tumor necrosis in colorectal cancer.

PubMed

Zhang, Xi; Chen, Lirong

2016-02-01

In colorectal cancer (CRC), despite the complex inducing and regulating mechanism in necrosis progress, the prognostic value of tumor necrosis has been reported. It is generally recognized that necrosis is associated with many process involving severe hypoxia, inflammatory responses and angiogenesis, all of which contribute to promote tumor growth and poor prognosis. In addition to local hypoxia, regulation by RIP kinase and the conversion from apoptosis to necrosis can result in necrosis also. Recent studies showed necrosis can be a histopathologic characteristic for special molecular phenotype of CRC. A novel and attractive complementary treatment, tumor necrosis therapy, using radiolabelled compounds avid for necrosis has emerged. However, the complicated regulatory mechanisms of tumor necrosis were rarely reported in CRC, and we collected and reviewed these effect and relevance in CRC.

Histone deacetylases as regulators of inflammation and immunity.

PubMed

Shakespear, Melanie R; Halili, Maria A; Irvine, Katharine M; Fairlie, David P; Sweet, Matthew J

2011-07-01

Histone deacetylases (HDACs) remove an acetyl group from lysine residues of target proteins to regulate cellular processes. Small-molecule inhibitors of HDACs cause cellular growth arrest, differentiation and/or apoptosis, and some are used clinically as anticancer drugs. In animal models, HDAC inhibitors are therapeutic for several inflammatory diseases, but exacerbate atherosclerosis and compromise host defence. Loss of HDAC function has also been linked to chronic lung diseases in humans. These contrasting effects might reflect distinct roles for individual HDACs in immune responses. Here, we review the current understanding of innate and adaptive immune pathways that are regulated by classical HDAC enzymes. The objective is to provide a rationale for targeting (or not targeting) individual HDAC enzymes with inhibitors for future immune-related applications. Copyright © 2011 Elsevier Ltd. All rights reserved.

The effect of TNFα secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells.

PubMed

Lee, Sang-Soo; Sharma, Ashish R; Choi, Byung-Soo; Jung, Jun-Sub; Chang, Jun-Dong; Park, Seonghun; Salvati, Eduardo A; Purdue, Edward P; Song, Dong-Keun; Nam, Ju-Suk

2012-06-01

Wear particles are the major cause of osteolysis associated with failure of implant following total joint replacement. During this pathologic process, activated macrophages mediate inflammatory responses to increase osteoclastogenesis, leading to enhanced bone resorption. In osteolysis caused by wear particles, osteoprogenitors present along with macrophages at the implant interface may play significant roles in bone regeneration and implant osteointegration. Although the direct effects of wear particles on osteoblasts have been addressed recently, the role of activated macrophages in regulation of osteogenic activity of osteoblasts has scarcely been studied. In the present study, we examined the molecular communication between macrophages and osteoprogenitor cells that may explain the effect of wear particles on impaired bone forming activity in inflammatory bone diseases. It has been demonstrated that conditioned medium of macrophages challenged with titanium particles (Ti CM) suppresses early and late differentiation markers of osteoprogenitors, including alkaline phosphatase (ALP) activity, collagen synthesis, matrix mineralization and expression of osteocalcin and Runx2. Moreover, bone forming signals such as WNT and BMP signaling pathways were inhibited by Ti CM. Interestingly, TNFα was identified as a predominant factor in Ti CM to suppress osteogenic activity as well as WNT and BMP signaling activity. Furthermore, Ti CM or TNFα induces the expression of sclerostin (SOST) which is able to inhibit WNT and BMP signaling pathways. It was determined that over-expression of SOST suppressed ALP activity, whereas the inhibition of SOST by siRNA partially restored the effect of Ti CM on ALP activity. This study highlights the role of activated macrophages in regulation of impaired osteogenic activity seen in inflammatory conditions and provides a potential mechanism for autocrine regulation of WNT and BMP signaling mediated by TNFα via induction of SOST in osteprogenitor cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shuai; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208; Lv, Jiaju

2012-03-30

Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responsesmore » in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNF{alpha}-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-{kappa}B activity, contributing to the pathogenesis of vascular disease.« less

Sinensetin attenuates LPS-induced inflammation by regulating the protein level of IκB-α.

PubMed

Shin, Hye-Sun; Kang, Seong-Il; Yoon, Seon-A; Ko, Hee-Chul; Kim, Se-Jae

2012-01-01

Sinensetin is one of the polymethoxyflavones (PMFs) having five methoxy groups on the basic benzo-γ-pyrone skeleton with a carbonyl group at the C(4) position. We investigated in this study the anti-inflammatory activity of sinensetin in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Sinensetin showed anti-inflammatory activity by regulating the protein level of inhibitor κB-α (IκB-α).

Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis.

PubMed

Camacho-Barquero, Laura; Villegas, Isabel; Sánchez-Calvo, Juan Manuel; Talero, Elena; Sánchez-Fidalgo, Susana; Motilva, Virginia; Alarcón de la Lastra, Catalina

2007-03-01

Ulcerative colitis (UC) is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and up-regulation of pro-inflammatory cytokines. Mitogen-activated protein kinases (MAPKs), such as the p38 and the c-Jun N-terminal kinase (JNK) modulate the transcription of many genes involved in the inflammatory process. Curcumin is a polyphenol derived from Curcuma longa, which is known to have anti-inflammatory activity. The aim of this study was to study the effects and mechanisms of action of curcumin, on chronic colitis in rats. Inflammation response was assessed by histology and myeloperoxidase activity (MPO). We determined the production of Th1 and Th2 cytokines and nitrites in colon mucosa, as well as the expression of inducible nitric oxide synthase (iNOS), cyclo-oxygenase(COX)-1 and-2 by western blotting and inmmunohistochemistry. Finally, we studied the involvement of MAPKs signaling in the protective effect of curcumin in chronic colonic inflammation. Curcumin (50-100 mg/kg/day) were administered by oral gavage 24 h after trinitrobenzensulfonic acid (TNBS) instillation, and daily during 2 weeks before sacrifice. Curcumin significantly attenuated the damage and caused substantial reductions of the rise in MPO activity and tumour necrosis factor alpha (TNF)-alpha. Also curcumine was able to reduce nitrites colonic levels and induced down-regulation of COX-2 and iNOS expression, and a reduction in the activation of p38 MAPK; however, no changes in the activation of JNK could be observed. In conclusion, we suggest that inhibition of p38 MAPK signaling by curcumin could explain the reduced COX-2 and iNOS immunosignals and the nitrite production in colonic mucosa reducing the development of chronic experimental colitis.

γδ T Cells Regulate the Early Inflammatory Response to Bordetella pertussis Infection in the Murine Respiratory Tract

PubMed Central

Zachariadis, O.; Cassidy, J. P.; Brady, J.; Mahon, B. P.

2006-01-01

The role of γδ T cells in the regulation of pulmonary inflammation following Bordetella pertussis infection was investigated. Using a well-characterized murine aerosol challenge model, inflammatory events in mice with targeted disruption of the T-cell receptor δ-chain gene (γδ TCR−/− mice) were compared with those in wild-type animals. Early following challenge with B. pertussis, γδ TCR−/− mice exhibited greater pulmonary inflammation, as measured by intra-alveolar albumin leakage and lesion histomorphometry, yet had lower contemporaneous bacterial lung loads. The larger numbers of neutrophils and macrophages and the greater concentration of the neutrophil marker myeloperoxidase in bronchoalveolar lavage fluid from γδ TCR−/− mice at this time suggested that differences in lung injury were mediated through increased leukocyte trafficking into infected alveoli. Furthermore, flow cytometric analysis found the pattern of recruitment of natural killer (NK) and NK receptor+ T cells into airspaces differed between the two mouse types over the same time period. Taken together, these findings suggest a regulatory influence for γδ T cells over the early pulmonary inflammatory response to bacterial infection. The absence of γδ T cells also influenced the subsequent adaptive immune response to specific bacterial components, as evidenced by a shift from a Th1 to a Th2 type response against the B. pertussis virulence factor filamentous hemagglutinin in γδ TCR−/− mice. The findings are relevant to the study of conditions such as neonatal B. pertussis infection and acute respiratory distress syndrome where γδ T cell dysfunction has been implicated in the inflammatory process. PMID:16495558

The immunosuppressive effects of a novel recombinant LipQ (Rv2485c) protein of Mycobacterium tuberculosis on human macrophage cell lines.

PubMed

Kumar, Anjani; Manisha; Sangha, Gurkamaljit Kaur; Shrivastava, Anju; Kaur, Jagdeep

2017-06-01

Mycobacterium tuberculosis (MTB), an intracellular pathogen, still represents a major global health challenge. A number of mycobacterial macromolecules have been shown to target biological processes within host macrophages; however, the exact mechanism for the majority of these host pathogen interactions is still poorly understood. Moreover, the lipid metabolic pathway is one of the most important physiologic pathways that plays a vital role in the survival and infection of Mycobacterium tuberculosis. In present study, we investigated the effect of rLipQ from Mycobacterium tuberculosis H37Rv on macrophage functions in vitro.Our results demonstrate that rLipQ significantly lowers the expression level of pro-inflammatory cytokines (TNF-α& IFN-γ) and augments the level of anti inflammatory cytokines such as IL-4 & IL-10as compared to LPS stimulated macrophages. An up-regulation of anti-inflammatory and down-regulation of pro-inflammatory cytokines levels in rLipQ pretreated macrophages implies immuno-modulatory functions in TB patients. Interestingly, rLipQ also inhibited the expression of iNOS, TLR-2 and transcription factor NF-kB in LPS stimulated macrophages whereas the expression of TLR-4 remains unchanged. The inhibition in the expression of these signaling molecules has been correlated to the inhibition of NO production in macrophages. Taken together, these studies demonstrate that rLipQ is a novel lipase that is highly immunogenic and may play an important role in the virulence and pathogenesis of M. tuberculosis infection, by altering the balance of cytokines, which might help to assess prognosis and contribute to a better understanding against host-pathogen interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulation of immunological and inflammatory functions by biotin.

PubMed

Kuroishi, Toshinobu

2015-12-01

Biotin is a water-soluble B-complex vitamin and is well-known as a co-factor for 5 indispensable carboxylases. Holocarboxylase synthetase (HLCS) catalyzes the biotinylation of carboxylases and other proteins, whereas biotinidase catalyzes the release of biotin from biotinylated peptides. Previous studies have reported that nutritional biotin deficiency and genetic defects in either HLCS or biotinidase induces cutaneous inflammation and immunological disorders. Since biotin-dependent carboxylases involve various cellular metabolic pathways including gluconeogenesis, fatty acid synthesis, and the metabolism of branched-chain amino acids and odd-chain fatty acids, metabolic abnormalities may play important roles in immunological and inflammatory disorders caused by biotin deficiency. Transcriptional factors, including NF-κB and Sp1/3, are also affected by the status of biotin, indicating that biotin regulates immunological and inflammatory functions independently of biotin-dependent carboxylases. An in-vivo analysis with a murine model revealed the therapeutic effects of biotin supplementation on metal allergies. The novel roles of biotinylated proteins and their related enzymes have recently been reported. Non-carboxylase biotinylated proteins induce chemokine production. HLCS is a nuclear protein involved in epigenetic and chromatin regulation. In this review, comprehensive knowledge on the regulation of immunological and inflammatory functions by biotin and its potential as a therapeutic agent is discussed.

An ethanol extract of Piper betle Linn. mediates its anti-inflammatory activity via down-regulation of nitric oxide.

PubMed

Ganguly, Sudipto; Mula, Soumyaditya; Chattopadhyay, Subrata; Chatterjee, Mitali

2007-05-01

The leaves of Piper betle (locally known as Paan) have long been in use in the Indian indigenous system of medicine for the relief of pain; however, the underlying molecular mechanisms of this effect have not been elucidated. The anti-inflammatory and immunomodulatory effects of an ethanolic extract of the leaves of P. betle (100 mg kg(-1); PB) were demonstrated in a complete Freund's adjuvant-induced model of arthritis in rats with dexamethasone (0.1 mg kg(-1)) as the positive control. At non-toxic concentrations of PB (5-25 microg mL(-1)), a dose-dependent decrease in extracellular production of nitric oxide in murine peritoneal macrophages was measured by the Griess assay and corroborated by flow cytometry using the nitric oxide specific probe, 4,5-diaminofluorescein-2 diacetate. This decreased generation of reactive nitrogen species was mediated by PB progressively down-regulating transcription of inducible nitric oxide synthase in macrophages, and concomitantly causing a dose-dependent decrease in the expression of interleukin-12 p40, indicating the ability of PB to down-regulate T-helper 1 pro-inflammatory responses. Taken together, the anti-inflammatory and anti-arthrotic activity of PB is attributable to its ability to down-regulate the generation of reactive nitrogen species, thus meriting further pharmacological investigation.

Immunomodulatory effect of CD200-positive human placenta-derived stem cells in the early phase of stroke

PubMed Central

Kong, TaeHo; Park, Ji-Min; Jang, Ji Hyon; Kim, C-Yoon; Bae, Sang-Hun; Choi, Yuri; Jeong, Yun-Hwa; Kim, Chul; Chang, Sung Woon; Kim, Joopyung; Moon, Jisook

2018-01-01

Human placenta amniotic membrane-derived mesenchymal stem cells (AMSCs) regulate immune responses, and this property can be exploited to treat stroke patients via cell therapy. We investigated the expression profile of AMSCs cultured under hypoxic conditions and observed interesting expression changes in various genes involved in immune regulation. CD200, an anti-inflammatory factor and positive regulator of TGF-β, was more highly expressed under hypoxic conditions than normoxic conditions. Furthermore, AMSCs exhibited inhibition of pro-inflammatory cytokine expression in co-cultures with LPS-primed BV2 microglia, and this effect was decreased in CD200-silenced AMSCs. The AMSCs transplanted into the ischemic rat model of stroke dramatically inhibited the expression of pro-inflammatory cytokines and up-regulated CD200, as compared with the levels in the sham-treated group. Moreover, decreased microglia activation in the boundary region and improvements in behavior were confirmed in AMSC-treated ischemic rats. The results suggested that the highly expressed CD200 from the AMSCs in a hypoxic environment modulates levels of inflammatory cytokines and microglial activation, thus increasing the therapeutic recovery potential after hypoxic-ischemic brain injury, and further demonstrated the immunomodulatory function of AMSCs in a stroke model. PMID:29328072

[The brain and cytokines - the mutual origin of depression, obesity and cardiovascular diseases?].

PubMed

Ufnal, Marcin; Wolynczyk-Gmaj, Dorota

2011-04-19

Accumulating evidence points to a pivotal role of the brain in the regulation of the circulatory system and energy balance. It has also been found that common civilization diseases such as depression, obesity, hypertension, myocardial infarction or heart failure are accompanied by an increase in concentration of inflammatory mediators in the blood, cerebrospinal fluid and various tissues. Recent studies have revealed that inflammatory mediators that are synthesized peripherally or in the brain may affect the nervous regulation of animal body systems. For example, it has been found that non-specific pro-inflammatory stimuli as well as treatment with several cytokines may cause depressive behavior, disturbances in energy balance and alterations in the circulatory system. On the other hand, knockout of genes for pro-inflammatory cytokines or administration of anti-inflammatory mediators may normalize the pathological changes. In the present manuscript we will review studies that imply the common neuroinflammatory pathogenesis of cardiovascular diseases, depression and energy balance disorders.

Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

PubMed Central

Papi, Alessio; Storci, Gianluca; Guarnieri, Tiziana; De Carolis, Sabrina; Bertoni, Sara; Avenia, Nicola; Sanguinetti, Alessandro; Sidoni, Angelo; Santini, Donatella; Ceccarelli, Claudio; Taffurelli, Mario; Orlandi, Marina; Bonafé, Massimiliano

2013-01-01

Aims Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells “inflammatory addiction” leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells. Methods Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts. Results In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. Conclusion Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning. PMID:23372804

Immunobiotic Lactobacillus jensenii Elicits Anti-Inflammatory Activity in Porcine Intestinal Epithelial Cells by Modulating Negative Regulators of the Toll-Like Receptor Signaling Pathway

PubMed Central

Shimazu, Tomoyuki; Villena, Julio; Tohno, Masanori; Fujie, Hitomi; Hosoya, Shoichi; Shimosato, Takeshi; Aso, Hisashi; Suda, Yoshihito; Kawai, Yasushi; Saito, Tadao; Makino, Seiya; Ikegami, Shuji; Itoh, Hiroyuki

2012-01-01

The effect of Lactobacillus jensenii TL2937 on the inflammatory immune response triggered by enterotoxigenic Escherichia coli (ETEC) and lipopolysaccharide (LPS) in a porcine intestinal epitheliocyte cell line (PIE cells) was evaluated. Challenges with ETEC or LPS elicited Toll-like receptor 4 (TLR4)-mediated inflammatory responses in cultured PIE cells, indicating that our cell line may be useful for studying inflammation in the guts of weaning piglets. In addition, we demonstrated that L. jensenii TL2937 attenuated the expression of proinflammatory cytokines and chemokines caused by ETEC or LPS challenge by downregulating TLR4-dependent nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we demonstrated that L. jensenii TL2937 stimulation of PIE cells upregulated three negative regulators of TLRs: A20, Bcl-3, and MKP-1, deepening the understanding of an immunobiotic mechanism of action. L. jensenii TL2937-mediated induction of negative regulators of TLRs would have a substantial physiological impact on homeostasis in PIE cells, because excessive TLR inflammatory signaling would be downregulated. These results indicated that PIE cells can be used to study the mechanisms involved in the protective activity of immunobiotics against intestinal inflammatory damage and may provide useful information for the development of new immunologically functional feeds that help to prevent inflammatory intestinal disorders, including weaning-associated intestinal inflammation. PMID:22083706

Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity

PubMed Central

Bollmann, Franziska; Art, Julia; Henke, Jenny; Schrick, Katharina; Besche, Verena; Bros, Matthias; Li, Huige; Siuda, Daniel; Handler, Norbert; Bauer, Florian; Erker, Thomas; Behnke, Felix; Mönch, Bettina; Härdle, Lorena; Hoffmann, Markus; Chen, Ching-Yi; Förstermann, Ulrich; Dirsch, Verena M.; Werz, Oliver; Kleinert, Hartmut; Pautz, Andrea

2014-01-01

Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol. PMID:25352548

Benzyl alcohol derivatives from the mushroom Hericium erinaceum attenuate LPS-stimulated inflammatory response through the regulation of NF-κB and AP-1 activity.

PubMed

Noh, Hyung Jun; Yoon, Ju Young; Kim, Geum Sook; Lee, Seung Eun; Lee, Dae Young; Choi, Je Hun; Kim, Seung Yu; Kang, Ki Sung; Cho, Jae Youl; Kim, Ki Hyun

2014-10-01

On the search for anti-inflammatory compounds from natural Korean medicinal sources, a bioassay-guided fractionation and chemical investigation of the MeOH extract from the fruiting bodies of Hericium erinaceum resulted in the isolation and identification of five benzyl alcohol derivatives (1-5). In this study, their anti-inflammatory effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators were examined using RAW 264.7 macrophage cells. The structures of isolates were identified by comparing their spectroscopic data with previously reported values. The analysis of their inhibitory activities on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophage cells showed that erinacerin B (2) and hericenone E (4) decreased the levels of NO and PGE2 production in a concentration-dependent manner. Next, this study was performed to examine their mechanism of action on the regulation of NO and PGE2 production. Compounds 2 and 4 were found to block the LPS-induced phosphorylation of two major inflammatory transcription factors, NF-κB (p65/p50) and AP-1 (c-Jun and c-Fos). Taken together, these results suggest that down-regulation of LPS-induced NO and PGE2 production by compounds 2 and 4 is mediated through the modulation of NF-κB and AP-1 activation in macrophage cells. These results impact the development of potential health products for preventing and treating inflammatory diseases.

Hyaluronic acid, an efficient biomacromolecule for treatment of inflammatory skin and joint diseases: A review of recent developments and critical appraisal of preclinical and clinical investigations.

PubMed

Chen, Li Hui; Xue, Jian Feng; Zheng, Zhi Yong; Shuhaidi, Muhammad; Thu, Hnin Ei; Hussain, Zahid

2018-05-18

Hyaluronic acid (HA) plays multifaceted role in regulating various biological processes and maintaining homeostasis into the body. Numerous researches evidenced the biomedical implications of HA in skin repairmen, cancer prognosis, wound healing, tissue regeneration, anti-inflammatory, immunomodulation. The present review was aimed to summarize and critically appraise the recent developments and efficacy of HA for treatment of inflammatory skin and joint diseases. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, autologous graft, thin sheets, soaked gauze, gauze pad, tincture, injection) have shown remarkable efficacy in treating a wide range of inflammatory skin diseases. The safety, tolerability, and efficacy of HA (as intra-articular injection) have also been well-documented for treatment of various types of joint disease including knee osteoarthritic, joint osteoarthritis, canine osteoarthritis, and meniscal swelling. Intra-articular injection of HA produces remarkable reduction in joint pain, synovial inflammation, and articular swelling. A remarkable improvement in chondrocyte density, territorial matrix appearance, reconstitution of superficial amorphous layer of the cartilage, collagen remodelling, and regeneration of meniscus have also been evident in patients treated with HA. Conclusively, we validate that the application/administration of HA is a promising pharmacotherapeutic regimen for treatment of inflammatory skin and joint diseases. Copyright © 2018. Published by Elsevier B.V.

Oak kombucha protects against oxidative stress and inflammatory processes.

PubMed

Vázquez-Cabral, B D; Larrosa-Pérez, M; Gallegos-Infante, J A; Moreno-Jiménez, M R; González-Laredo, R F; Rutiaga-Quiñones, J G; Gamboa-Gómez, C I; Rocha-Guzmán, N E

2017-06-25

Black tea infusion is the common substrate for preparing kombucha; however other sources such as oak leaves infusions can be used for the same purpose. Almost any white oak species have been used for medicinal applications by some ethnic groups in Mexico and could be also suitable for preparing kombucha analogues from oak (KAO). The objective of this research was to investigate the antioxidant activity and anti-inflammatory effects of KAO by examining its modulation ability on macrophage-derived TNF-alpha and IL-6. Herbal infusions from oak and black tea were fermented by kombucha consortium during seven days at 28 °C. Chemical composition was determined by LC-ESI-MS/MS. The antioxidant activity of samples against oxidative damage caused by H 2 O 2 in monocytes activated (macrophages) was explored. Additionally, it was determined the anti-inflammatory activity using lipopolysaccharide (LPS) - stimulated macrophages; in particular, the nitric oxide (NO), TNF-alpha, and IL-6 production was assessed. Levels of pro-inflammatory cytokines IL-6 and TNF-alpha were significantly reduced by the sample treatment. Likewise, NO production was lower in treatment with kombucha and KAO compared with LPS-stimulated macrophages. Fermented beverages of oak effectively down-regulated the production of NO, while pro-inflammatory cytokines (TNF-alpha and IL-6) in macrophages were stimulated with LPS. Additionally, phytochemical compounds present in KAO decrease oxidative stress. Copyright © 2017 Elsevier B.V. All rights reserved.

Fatigue and gene expression in human leukocytes: Increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

PubMed Central

Bower, Julienne E.; Ganz, Patricia A.; Irwin, Michael R.; Arevalo, Jesusa M.G.; Cole, Steve W.

2013-01-01

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n = 11) and non-fatigued controls (n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID:20854893

Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats.

PubMed

Marín-Prida, Javier; Pavón-Fuentes, Nancy; Llópiz-Arzuaga, Alexey; Fernández-Massó, Julio R; Delgado-Roche, Liván; Mendoza-Marí, Yssel; Santana, Seydi Pedroso; Cruz-Ramírez, Alieski; Valenzuela-Silva, Carmen; Nazábal-Gálvez, Marcelo; Cintado-Benítez, Alberto; Pardo-Andreu, Gilberto L; Polentarutti, Nadia; Riva, Federica; Pentón-Arias, Eduardo; Pentón-Rol, Giselle

2013-10-01

Since the inflammatory response and oxidative stress are involved in the stroke cascade, we evaluated here the effects of Phycocyanobilin (PCB, the C-Phycocyanin linked tetrapyrrole) on PC12 cell survival, the gene expression and the oxidative status of hypoperfused rat brain. After the permanent bilateral common carotid arteries occlusion (BCCAo), the animals were treated with saline or PCB, taking samples 24h post-surgery. Global gene expression was analyzed with GeneChip Rat Gene ST 1.1 from Affymetrix; the expression of particular genes was assessed by the Fast SYBR Green RT-PCR Master Mix and Bioplex methods; and redox markers (MDA, PP, CAT, SOD) were evaluated spectrophotometrically. The PCB treatment prevented the H2O2 and glutamate induced PC12 cell injury assessed by the MTT assay, and modulated 190 genes (93 up- and 97 down-regulated) associated to several immunological and inflammatory processes in BCCAo rats. Furthermore, PCB positively modulated 19 genes mostly related to a detrimental pro-inflammatory environment and counteracted the oxidative imbalance in the treated BCCAo animals. Our results support the view of an effective influence of PCB on major inflammatory mediators in acute cerebral hypoperfusion. These results suggest that PCB has a potential to be a treatment for ischemic stroke for which further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies.

PubMed

West, Christina E; Renz, Harald; Jenmalm, Maria C; Kozyrskyj, Anita L; Allen, Katrina J; Vuillermin, Peter; Prescott, Susan L

2015-01-01

Rapid environmental transition and modern lifestyles are likely driving changes in the biodiversity of the human gut microbiota. With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated noncommunicable diseases (NCDs). There are also suggestive implications for neurodevelopment and mental health. These diverse multisystem influences have sparked interest in strategies that might favorably modulate the gut microbiota to reduce the risk of many NCDs. For example, specific prebiotics promote favorable intestinal colonization, and their fermented products have anti-inflammatory properties. Specific probiotics also have immunomodulatory and metabolic effects. However, when evaluated in clinical trials, the effects are variable, preliminary, or limited in magnitude. Fecal microbiota transplantation is another emerging therapy that regulates inflammation in experimental models. In human subjects it has been successfully used in cases of Clostridium difficile infection and IBD, although controlled trials are lacking for IBD. Here we discuss relationships between gut colonization and inflammatory NCDs and gut microbiota modulation strategies for their treatment and prevention. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation

PubMed Central

Meyer, Alain; Laverny, Gilles; Bernardi, Livio; Charles, Anne Laure; Alsaleh, Ghada; Pottecher, Julien; Sibilia, Jean; Geny, Bernard

2018-01-01

Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation. PMID:29725325

Regulation of RAW 264.7 macrophages behavior on anodic TiO2 nanotubular arrays

NASA Astrophysics Data System (ADS)

Yao, Shenglian; Feng, Xujia; Li, Wenhao; Wang, Lu-Ning; Wang, Xiumei

2017-12-01

Titanium (Ti) implants with TiO2 nanotubular arrays on the surface could regulate cells adhesion, proliferation and differentiation to determine the bone integration. Additionally, the regulation of immune cells could improve osteogenesis or lead in appropriate immune reaction. Thus, we evaluate the behavior of RAW264.7 macrophages on TiO2 nanotubular arrays with a wide range diameter (from 20 to 120 nm) fabricated by an electrochemical anodization process. In this work, the proliferation, cell viability and cytokine/chemokine secretion were evaluated by CCK-8, live/dead staining and ELISA, respectively. SEM and confocal microscopy were used to observe the adhesion morphology. Results showed that the small size nanotube surface was benefit for the macrophages adhesion and proliferation, while larger size surface could reduce the inflammatory response. These findings contribute to the design of immune-regulating Ti implants surface that supports successful implantation.

Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells.

PubMed

El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George; Connell, Terry D; Nashar, Toufic O

2016-12-01

Cholecystokinin (CCK) is a neuropeptide that affects growth rate in chickens by regulating appetite. CCK peptides exert their function by binding to two identified receptors, CCKAR and CCKBR in the GI tract and the brain, respectively, as well as in other organs. In mammals, CCK/CCKAR interactions affect a number of immunological parameters, including regulation of lymphocytes and functioning of monocytes. Thus, food intake and growth can potentially be altered by infection and the resulting inflammatory immune response. It is uncertain, however, whether chicken express CCKAR in immune organs and cells, and, if so, whether CCKAR expression is regulated by pathogen derived inflammatory stimuli. Herein, we identify expression of CCKAR protein in chicken peripheral blood mononuclear cells (PBMC) including monocytes, and expression of the CCKAR gene in PBMC, thymus, bursa, and spleen, in selected commercial and pure chicken breeds. Further, stimulation with various types of E. coli heat-labile enterotoxins or lipopolysaccharide significantly regulated expression of CCKAR on monocytes in the different breeds. Ligation of CCKAR with antibodies in PBMC induced mobilization of Ca 2+ , indicating that CCKAR is signal competent. Injection with polyinosinic: polycytidylic acid (poly I:C), a synthetic analogue of double stranded viral RNA that binds Toll-Like Receptor-3 (TLR3), also regulated gene expressions of CCKAR and proinflammatory cytokines, in the different breeds. Interestingly, variations in the expression levels of proinflammatory cytokines in the different breeds were highly correlated with CCKAR expression levels. Taken together, these findings indicate that the physiological function of CCKAR in the chicken is tightly regulated in immune organs and cells by external inflammatory stimuli, which in turn regulate growth. This is the first report CCKAR expression in immune organs and cells, in any species, and the initial observation that CCKAR is regulated by inflammatory stimuli associated with bacterial and viral infection.

Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells

PubMed Central

El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George; Connell, Terry D; Nashar, Toufic O

2017-01-01

Cholecystokinin (CCK) is a neuropeptide that affects growth rate in chickens by regulating appetite. CCK peptides exert their function by binding to two identified receptors, CCKAR and CCKBR in the GI tract and the brain, respectively, as well as in other organs. In mammals, CCK/CCKAR interactions affect a number of immunological parameters, including regulation of lymphocytes and functioning of monocytes. Thus, food intake and growth can potentially be altered by infection and the resulting inflammatory immune response. It is uncertain, however, whether chicken express CCKAR in immune organs and cells, and, if so, whether CCKAR expression is regulated by pathogen derived inflammatory stimuli. Herein, we identify expression of CCKAR protein in chicken peripheral blood mononuclear cells (PBMC) including monocytes, and expression of the CCKAR gene in PBMC, thymus, bursa, and spleen, in selected commercial and pure chicken breeds. Further, stimulation with various types of E. coli heat-labile enterotoxins or lipopolysaccharide significantly regulated expression of CCKAR on monocytes in the different breeds. Ligation of CCKAR with antibodies in PBMC induced mobilization of Ca2+, indicating that CCKAR is signal competent. Injection with polyinosinic: polycytidylic acid (poly I:C), a synthetic analogue of double stranded viral RNA that binds Toll-Like Receptor-3 (TLR3), also regulated gene expressions of CCKAR and proinflammatory cytokines, in the different breeds. Interestingly, variations in the expression levels of proinflammatory cytokines in the different breeds were highly correlated with CCKAR expression levels. Taken together, these findings indicate that the physiological function of CCKAR in the chicken is tightly regulated in immune organs and cells by external inflammatory stimuli, which in turn regulate growth. This is the first report CCKAR expression in immune organs and cells, in any species, and the initial observation that CCKAR is regulated by inflammatory stimuli associated with bacterial and viral infection. PMID:28149670

Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Wei; Gao, Yang; Chang, Na

The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2more » antibody and dramatically reversed by CCL2. Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. - Highlights: • Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. • Nurr1 overexpression inhibited apoptosis, release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells. • CCL2 reversed the effect of Nurr1 overexpression on apoptosis, inflammatory cytokines secretion and viability. • Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. • Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits.« less

Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases

PubMed Central

Zhai, Yuankun; Tyagi, Suresh C.; Tyagi, Neetu

2017-01-01

Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H2S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H2S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H2S mitigates bone diseases are not completely understood. Experimental evidence suggests that H2S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H2S biosynthesis. The inter-regulation of microRNAs and H2S opens a new possibility for exploring the H2S-microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H2S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H2S mediated bone loss inhibition, H2S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H2S as a therapeutic agent for bone diseases. PMID:28618652

Inflammatory response in rat lungs with recurrent exposure to welding fumes: a transcriptomic approach.

PubMed

Oh, Jung-Hwa; Yang, Mi-Jin; Heo, Jeong-Doo; Yang, Young-Su; Park, Han-Jin; Park, Se-Myo; Kwon, Myung-Sang; Song, Chang-Woo; Yoon, Seokjoo; Yu, Il Je

2012-04-01

As chronic exposure to welding fumes causes pulmonary diseases, such as pneumoconiosis, public concern has increased regarding continued exposure to these hazardous gases in the workplace. In a previous study, the inflammatory response to welding fume exposure was analysed in rat lungs in the case of recurrent exposure and recovery periods. Thus using lung samples, well-annotated by histological observation and biochemical analysis, this study examines the gene expression profiles to identify phenotype-anchored genes corresponding to lung inflammation and the repair phenomenon after recurrent welding fume exposure. Seven genes (Mmp12, Cd5l, LOC50101, LOC69183, Spp1, and Slc26a4) were found to be significantly up-regulated according to the severity of the lung injury. In addition, the transcription and translation of Trem2, which was up-regulated in response to the repair process, were validated using a real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The differentially expressed genes in the exposure and recovery groups were also classified using k-means and hierarchical clustering, plus their toxicological function and canonical pathways were further analysed using Ingenuity Pathways Analysis Software. As a result, this comprehensive and integrative analysis of the transcriptional changes that occur during repeated exposure provides important information on the inflammation and repair processes after welding-fume-induced lung injury.

The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mandal, Mili, E-mail: milimandal@gmail.com

Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b{sup +} infiltrating Ly6G{sup +} granulocytic and Ly6G{sup −} monocytic cells in the spleen and the liver. The majority of the Ly6G{sup +} cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G{sup −} cells consisted of 3 subpopulations expressingmore » high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80{sup +}) and immature (F4/80{sup −}) pro-inflammatory Ly6C{sup hi} macrophages and mature anti-inflammatory (Ly6C{sup lo}) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3{sup +} macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the bone marrow. • Hepatotoxicity is reduced in splenectomized mice.« less

The cytokine temporal profile in rat cortex after controlled cortical impact

PubMed Central

Dalgard, Clifton L.; Cole, Jeffrey T.; Kean, William S.; Lucky, Jessica J.; Sukumar, Gauthaman; McMullen, David C.; Pollard, Harvey B.; Watson, William D.

2012-01-01

Cerebral inflammatory responses may initiate secondary cascades following traumatic brain injury (TBI). Changes in the expression of both cytokines and chemokines may activate, regulate, and recruit innate and adaptive immune cells associated with secondary degeneration, as well as alter a host of other cellular processes. In this study, we quantified the temporal expression of a large set of inflammatory mediators in rat cortical tissue after brain injury. Following a controlled cortical impact (CCI) on young adult male rats, cortical and hippocampal tissue of the injured hemisphere and matching contralateral material was harvested at early (4, 12, and 24 hours) and extended (3 and 7 days) time points post-procedure. Naïve rats that received only anesthesia were used as controls. Processed brain homogenates were assayed for chemokine and cytokine levels utilizing an electrochemiluminescence-based multiplex ELISA platform. The temporal profile of cortical tissue samples revealed a multi-phasic injury response following brain injury. CXCL1, IFN-γ, TNF-α levels significantly peaked at four hours post-injury compared to levels found in naïve or contralateral tissue. CXCL1, IFN-γ, and TNF-α levels were then observed to decrease at least 3-fold by 12 hours post-injury. IL-1β, IL-4, and IL-13 levels were also significantly elevated at four hours post-injury although their expression did not decrease more than 3-fold for up to 24 hours post-injury. Additionally, IL-1β and IL-4 levels displayed a biphasic temporal profile in response to injury, which may suggest their involvement in adaptive immune responses. Interestingly, peak levels of CCL2 and CCL20 were not observed until after four hours post-injury. CCL2 levels in injured cortical tissue were significantly higher than peak levels of any other inflammatory mediator measured, thus suggesting a possible use as a biomarker. Fully elucidating chemokine and cytokine signaling properties after brain injury may provide increased insight into a number of secondary cascade events that are initiated or regulated by inflammatory responses. PMID:22291617

The cytokine temporal profile in rat cortex after controlled cortical impact.

PubMed

Dalgard, Clifton L; Cole, Jeffrey T; Kean, William S; Lucky, Jessica J; Sukumar, Gauthaman; McMullen, David C; Pollard, Harvey B; Watson, William D

2012-01-01

Cerebral inflammatory responses may initiate secondary cascades following traumatic brain injury (TBI). Changes in the expression of both cytokines and chemokines may activate, regulate, and recruit innate and adaptive immune cells associated with secondary degeneration, as well as alter a host of other cellular processes. In this study, we quantified the temporal expression of a large set of inflammatory mediators in rat cortical tissue after brain injury. Following a controlled cortical impact (CCI) on young adult male rats, cortical and hippocampal tissue of the injured hemisphere and matching contralateral material was harvested at early (4, 12, and 24 hours) and extended (3 and 7 days) time points post-procedure. Naïve rats that received only anesthesia were used as controls. Processed brain homogenates were assayed for chemokine and cytokine levels utilizing an electrochemiluminescence-based multiplex ELISA platform. The temporal profile of cortical tissue samples revealed a multi-phasic injury response following brain injury. CXCL1, IFN-γ, TNF-α levels significantly peaked at four hours post-injury compared to levels found in naïve or contralateral tissue. CXCL1, IFN-γ, and TNF-α levels were then observed to decrease at least 3-fold by 12 hours post-injury. IL-1β, IL-4, and IL-13 levels were also significantly elevated at four hours post-injury although their expression did not decrease more than 3-fold for up to 24 hours post-injury. Additionally, IL-1β and IL-4 levels displayed a biphasic temporal profile in response to injury, which may suggest their involvement in adaptive immune responses. Interestingly, peak levels of CCL2 and CCL20 were not observed until after four hours post-injury. CCL2 levels in injured cortical tissue were significantly higher than peak levels of any other inflammatory mediator measured, thus suggesting a possible use as a biomarker. Fully elucidating chemokine and cytokine signaling properties after brain injury may provide increased insight into a number of secondary cascade events that are initiated or regulated by inflammatory responses.

The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain.

PubMed

Griffiths, Mark R; Gasque, Philippe; Neal, James W

2009-03-01

Central nervous system (CNS) tissues contain cells (i.e. glia and neurons) that have innate immune functions. These cells express a range of receptors that are capable of detecting and clearing apoptotic cells and regulating inflammatory responses. Phagocytosis of apoptotic cells is a nonphlogistic (i.e. noninflammatory) process that provides immune regulation through anti-inflammatory cytokines andregulatory T cells. Neurons and glia express cellular death signals, including CD95Fas/CD95L, FasL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor receptor 1 (TNFR), through which they can trigger apoptosis in T cells and other infiltrating cells. Microglia, astrocytes, ependymal cells, and neurons express defense collagens and scavenger and phagocytic receptors that recognize apoptotic cells displaying apoptotic cell-associated molecular patterns, which serve as markers of "altered self." Glia also express pentraxins and complement proteins (C1q, C3b, and iC3b) that opsonize apoptotic cells, making them targets for the phagocytic receptors CR3 and CR4. Immunoregulatory molecules such as the complement regulator CD46 are lost from apoptotic cells and stimulate phagocytosis, whereas the expression of CD47 and CD200 is upregulated during apoptosis; this inhibits proinflammatory microglial cytokine expression, thereby reducing the severity of inflammation. This review outlines the cellular pathways used for the detection and phagocytosis of apoptotic cells in vitro and in experimental models of CNS inflammation.

The bromodomain protein BRD4 regulates splicing during heat shock.

PubMed

Hussong, Michelle; Kaehler, Christian; Kerick, Martin; Grimm, Christina; Franz, Alexandra; Timmermann, Bernd; Welzel, Franziska; Isensee, Jörg; Hucho, Tim; Krobitsch, Sylvia; Schweiger, Michal R

2017-01-09

The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling.

PubMed

Shen, Huiyun; Oesterling, Elizabeth; Stromberg, Arnold; Toborek, Michal; MacDonald, Ruth; Hennig, Bernhard

2008-10-01

Marginal intake of dietary zinc can be associated with increased risk of cardiovascular diseases. In the current study we hypothesized that vascular dysfunction and associated inflammatory events are activated during a zinc deficient state. We tested this hypothesis using both vascular endothelial cells and mice lacking the functional LDL-receptor gene. Zinc deficiency increased oxidative stress and NF-kappaB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-kappaB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-kappaB signaling. PPAR can inhibit NF-kappaB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARalpha expression in cultured endothelial cells. Furthermore, the PPARgamma agonist rosiglitazone was unable to inhibit the adhesion of monocytes to endothelial cells during zinc deficiency, an event which could be reversed by zinc supplementation. Our in vivo data support the importance of PPAR dysregulation during zinc deficiency. For example, rosiglitazone induced inflammatory genes (e.g., MCP-1) only during zinc deficiency, and adequate zinc was required for rosiglitazone to down-regulate pro-inflammatory markers such as iNOS. In addition, rosiglitazone increased IkappaBalpha protein expression only in zinc adequate mice. Finally, plasma data from LDL-R-deficient mice suggest an overall pro-inflammatory environment during zinc deficiency and support the concept that zinc is required for proper anti-inflammatory or protective functions of PPAR. These studies suggest that zinc nutrition can markedly modulate mechanisms of the pathology of inflammatory diseases such as atherosclerosis.

Thunbergia alata inhibits inflammatory responses through the inactivation of ERK and STAT3 in macrophages.

PubMed

Cho, Young-Chang; Kim, Ye Rang; Kim, Ba Reum; Bach, Tran The; Cho, Sayeon

2016-11-01

Thunbergia alata (Acanthaceae) has been used traditionally to treat various inflammatory diseases such as fever, cough and diarrhea in East African countries including Uganda and Kenya. However, systemic studies elucidating the anti-inflammatory effects and precise mechanisms of action of T. alata have not been conducted, to the best of our knowledge. To address these concerns, we explored the anti-inflammatory effects of a methanol extract of T. alata (MTA) in macrophages. Non-cytotoxic concentrations of MTA (≤300 µg/ml) inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)‑stimulated RAW 264.7 macrophages by transcriptional regulation of inducible NO synthase in a dose-dependent manner. The expression of cyclooxygenase-2, the enzyme responsible for the production of prostaglandin E2, was unchanged by MTA at the mRNA and protein levels. MTA treatment inhibited interleukin (IL)-6 production and decreased the mRNA expression of pro‑inflammatory cytokines, including IL-6 and IL-1β. Tumor necrosis factor-α production and mRNA expression were not regulated by MTA treatment. The decreased production of inflammatory mediators by MTA was followed by the reduced phosphorylation of extracellular signal‑regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3). MTA treatment had no effect on activity of other mitogen‑activated protein kinases (MAPKs), p38, c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These results indicate that MTA selectively inhibits the excessive production of inflammatory mediators in LPS-stimulated murine macrophages by reducing the activity of ERK and STAT3, suggesting that MTA plays an important inhibitory role in the modulation of severe inflammation.

A potential therapeutic role for aldose reductase inhibitors in the treatment of endotoxin-related inflammatory diseases

PubMed Central

Pandey, Saumya; Srivastava, Satish K

2012-01-01

Introduction Aldose reductase (AR) initially thought to be involved in the secondary diabetic complications because of its glucose reducing potential. However, evidence from recent studies indicates that AR is an excellent reducer of a number of lipid peroxidation-derived aldehydes as well as their glutathione conjugates, which regulate inflammatory signals initiated by oxidants such as cytokines, growth factors and bacterial endotoxins, and revealed the potential use of AR inhibition as an approach to prevent inflammatory complications. Areas covered An extensive Internet and Medline search was performed to retrieve information on understanding the role of AR inhibition in the pathophysiology of endotoxin-mediated inflammatory disorders. Overall, inhibition of AR appears to be a promising strategy for the treatment of endotoxemia, sepsis and other related inflammatory diseases. Expert opinion Current knowledge provides enough evidence to indicate that AR inhibition is a logical therapeutic strategy for the treatment of endotoxin-related inflammatory diseases. Since, AR inhibitors have already gone to Phase-iii clinical studies for diabetic complications and found to be safe for human use, their use in endotoxin–related inflammatory diseases could be expedited. However, one of the major challenges will be the discovery of AR regulated clinically-relevant biomarkers to identify susceptible individuals at risk of developing inflammatory diseases, thereby warranting future research in this area. PMID:22283786

Chagas disease: modulation of the inflammatory response by acetylcholinesterase in hematological cells and brain tissue.

PubMed

Silva, Aniélen D; Bottari, Nathieli B; do Carmo, Guilherme M; Baldissera, Matheus D; Souza, Carine F; Machado, Vanessa S; Morsch, Vera M; Schetinger, Maria Rosa C; Mendes, Ricardo E; Monteiro, Silvia G; Da Silva, Aleksandro S

2018-01-01

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.

Regulation of bitter taste responses by tumor necrosis factor.

PubMed

Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

2015-10-01

Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Regulation of bitter taste responses by tumor necrosis factor

PubMed Central

Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A.; Huang, Liquan; Wang, Hong

2015-01-01

Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. PMID:25911043

SncRNA (microRNA & snoRNA) opposite expression pattern found in multiple sclerosis relapse and remission is sex dependent

PubMed Central

Muñoz-Culla, Maider; Irizar, Haritz; Sáenz-Cuesta, Matías; Castillo-Triviño, Tamara; Osorio-Querejeta, Iñaki; Sepúlveda, Lucía; López de Munain, Adolfo; Olascoaga, Javier; Otaegui, David

2016-01-01

Multiple sclerosis (MS) is a common inflammatory and degenerative disease that causes neurological disability. It affects young adults and its prevalence is higher in women. The most common form is manifested as a series of acute episodes of neurological disability (relapses) followed by a recovery phase (remission). Recently, non-coding RNAs have emerged as new players in transcriptome regulation, and in turn, they could have a significant role in MS pathogenesis. In this context, our aim was to investigate the involvement of microRNAs and snoRNAs in the relapse-remission dynamics of MS in peripheral blood leucocytes, to shed light on the molecular and regulatory mechanisms that underlie this complex process. With this approach, we found that a subset of small non-coding RNAs (sncRNA) is altered in relapse and remission, revealing unexpected opposite changes that are sex dependent. Furthermore, we found that a relapse-related miRNA signature regulated general metabolism processes in leucocytes, and miRNA altered in remission are involved in the regulation of innate immunity. We observed that sncRNA dysregulation is different in relapse and remission leading to differences in transcriptome regulation, and that this process is sex dependent. In conclusion, relapse and remission have a different molecular background in men and women. PMID:26831009

[Epithelial mesenchymal transition in airway remodeling of asthma and its molecular regulation].

PubMed

Zhu, Xiaohua; Li, Qiugen

2018-05-28

Asthma is a chronic inflammatory disease of the airway. Repeated inflammatory injury and tissue repair can lead to airway remodeling. The airway epithelial mesenchymal transformation (EMT) plays an important role in airway remodeling of asthma. Various cytokines and signaling pathways, such as transforming growth factor β (TGF-β), nuclear factor-kappa B (NF-κB) and bromodomain-containing protein 4 (BRD4), are involved in the molecular regulation of EMT.

P2X receptor characterization and IL-1/IL-1Ra release from human endothelial cells.

PubMed

Wilson, H L; Varcoe, R W; Stokes, L; Holland, K L; Francis, S E; Dower, S K; Surprenant, A; Crossman, D C

2007-05-01

The pro-inflammatory cytokine, interleukin-1beta (IL-1beta), has been implicated in the pathogenesis of atherosclerosis, potentially via its release from vascular endothelium. Endothelial cells (EC) synthesize IL-1beta in response to inflammatory stimuli, but the demonstration and mechanism of release of IL-1 from ECs remains unclear. In activated monocytes, efficient release of bioactive IL-1beta occurred via activation of ATP-gated P2X(7) receptors (P2X(7)Rs). Activation of P2X(7)R in ECs from human umbilical vein (HUVECs) released IL-1 receptor antagonist (IL-1Ra). The purpose of this study was to provide a quantitative investigation of P2XR expression and function, in parallel with IL-1beta and IL-1Ra synthesis, processing and release, in HUVECs under pro-inflammatory conditions. Quantitative RT-PCR, immunoblotting, ELISA, flow cytometry, and whole-cell patch clamp recordings were used to determine protein expression and receptor function. IL-8-luciferase-reporter was used as an IL-1 sensitive bioassay. HUVECs expressed P2X(4)R and P2X(7)R subtypes and both were significantly up-regulated under inflammatory conditions. P2X(7)R currents were increased 3-fold by inflammatory stimuli, whereas no P2X(4)R-mediated currents were detected. Caspase-1, but not IL-1beta, was present intracellularly under basal conditions; inflammatory stimuli activated the synthesis of intracellular pro-IL-1beta and increased caspase-1 levels. Activation of P2X(7)Rs resulted in low-level release of bioactive IL-1beta and simultaneous release of IL-1Ra. The net biological effect of release was anti-inflammatory. Endothelial P2X(7)Rs induced secretion of both pro- and anti-inflammatory IL-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the arterial vessel wall.

Spatiotemporal expression dynamics of selectins govern the sequential extravasation of neutrophils and monocytes in the acute inflammatory response.

PubMed

Zuchtriegel, Gabriele; Uhl, Bernd; Hessenauer, Maximilian E T; Kurz, Angela R M; Rehberg, Markus; Lauber, Kirsten; Krombach, Fritz; Reichel, Christoph A

2015-04-01

Leukocyte recruitment to the site of inflammation is a key event in a variety of cardiovascular pathologies. Infiltrating neutrophils constitute the first line of defense that precedes a second wave of emigrating monocytes reinforcing the inflammatory reaction. The mechanisms initiating this sequential process remained largely obscure. Using advanced in vivo microscopy and in vitro/ex vivo techniques, we identified individual spatiotemporal expression patterns of selectins and their principal interaction partners on neutrophils, resident/inflammatory monocytes, and endothelial cells. Coordinating the intraluminal trafficking of neutrophils and inflammatory monocytes to common sites of extravasation, selectins assign different sites to these immune cells for their initial interactions with the microvascular endothelium. Whereas constitutively expressed leukocyte L-selectin/CD62L and endothelial P-selectin/CD62P together with CD44 and P-selectin glycoprotein ligand-1/CD162 initiate the emigration of neutrophils, de novo synthesis of endothelial E-selectin/CD62E launches the delayed secondary recruitment of inflammatory monocytes. In this context, P-selectin/CD62P and L-selectin/CD62L together with P-selectin glycoprotein ligand-1/CD162 and CD44 were found to regulate the flux of rolling neutrophils and inflammatory monocytes, whereas E-selectin/CD62E selectively adjusts the rolling velocity of inflammatory monocytes. Moreover, selectins and their interaction partners P-selectin glycoprotein ligand-1/CD162 and CD44 differentially control the intraluminal crawling behavior of neutrophils and inflammatory monocytes collectively enabling the sequential extravasation of these immune cells to inflamed tissue. Our findings provide novel insights into the mechanisms initiating the sequential infiltration of the perivascular tissue by neutrophils and monocytes in the acute inflammatory response and might thereby contribute to the development of targeted therapeutic strategies for prevention and treatment of cardiovascular diseases. © 2015 American Heart Association, Inc.

Systemic Inflammatory Load in Young and Old Ringdoves Is Modulated by Consumption of a Jerte Valley Cherry-Based Product

PubMed Central

Delgado, Jonathan; Terrón, María del Pilar; Garrido, María; Barriga, Carmen; Paredes, Sergio Damián; Espino, Javier

2012-01-01

Abstract A chronic subclinical inflammatory status that coexists with immune dysfunction is commonly found in the elderly population. Consumption of foods rich in antioxidants (e.g., cherries) is an attractive strategy to reduce risk from chronic diseases. Based on previous studies showing the antioxidant effect of a Jerte Valley cherry derivative product in humans, the objective of this work was to evaluate the effect of the intake of a Jerte Valley cherry-based beverage on inflammatory load in both young and old ringdoves (Streptopelia risoria). To this purpose, circulating levels of pro-inflammatory and anti-inflammatory cytokines as well as serum levels of different acute-phase proteins were measured before and after a 10-day treatment with the Jerte Valley cherry-based beverage. Thus, the 10-day treatment with the cherry-based beverage modulated the balance of pro- and anti-inflammatory cytokines in both young and old ringdoves by down-regulating the levels of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor-α, and interferon-γ) and up-regulating the levels of anti-inflammatory cytokines (IL-4, IL-2, and IL-10). Moreover, the 10-day treatment with the Jerte Valley cherry-based product reduced the levels of several proteins involved in acute-phase responses, such as C-reactive protein, haptoglobin, α2-macroglobulin, and serum amyloid P component. On the other hand, old birds showed imbalanced levels of inflammatory markers toward a pro-inflammatory status, thereby underlining the fact that aging is usually accompanied by systemic inflammation and inflammation-related chronic diseases. To sum up, the data suggest a potential health benefit by consuming the cherry-based beverage, especially in aged populations, through their anti-inflammatory properties. PMID:22846077

Progranulin Protects Vascular Endothelium against Atherosclerotic Inflammatory Reaction via Akt/eNOS and Nuclear Factor-κB Pathways

PubMed Central

Hwang, Hwan-Jin; Jung, Tae Woo; Hong, Ho Cheol; Choi, Hae Yoon; Seo, Ji-A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

2013-01-01

Objective Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described. Method and Results Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. Conclusion Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis. PMID:24098801

Sexual Dimorphism in Periapical Inflammation and Bone Loss from MAP Kinase Phosphatase-1 Deficient Mice

PubMed Central

McAbee, Justin; Li, Qiyan; Yu, Hong; Kirkwood, Keith L.

2012-01-01

Introduction Mitogen Activating Protein (MAPK) kinase phosphatase-1 (MKP-1) has been shown to be a key negative regulator of the MAP kinase pathways of the innate immune system. The impact of MKP-1 in an endodontic model has yet to be studied. Thus, the purpose of this study was to determine the role of MKP-1 in a bacterial-driven model of pathological endodontic bone loss. Methods Pulps were exposed in both lower 1st molars of 10-week old mkp-1+/+ and mkp-1−/− mice and left open to the oral environment for either 3 or 8 weeks. At sacrifice, mandibles were harvested and scanned by microcomputed tomography (μCT) to determine periapical bone loss. Histopathological scoring was then performed on the samples to determine the amount of inflammatory infiltrate within the periapical microenvironment. Results Significant bone loss and inflammatory infiltrate were found in all experimental groups when compared to control. No statistical difference was found between mkp-1+/+ and mkp-1−/− at either time point with respect to bone loss or inflammatory infiltrate. At 8 weeks, male mkp-1−/− mice were found to have significantly more bone loss and inflammatory infiltrate when compared to female mkp-1−/− mice. There was also a significant correlation between an increase in bone loss and increase in inflammatory infiltrate. Conclusions A sexual dimorphism exists in the periapical inflammatory process, where male mkp-1−/− mice have more inflammation than female mkp-1−/− mice. The increase in inflammatory infiltrate correlates to more bone loss in the male mice. PMID:22794213

Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis

DTIC Science & Technology

2015-10-01

1 AWARD NUMBER: W81XWH-14-1-0314 TITLE: Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis ...19 Sep 2015 4. TITLE AND SUBTITLE Glucocorticoid Receptor-Mediated Repression of Pro- Inflammatory Genes in Rheumatoid Arthritis 5a. CONTRACT NUMBER...SUBJECT TERMS Rheumatoid arthritis , inflammation and autoimmunity, macrophages, glucocorticoid receptor, transcriptional regulation, coactivators and

Mirtron microRNA-1236 inhibits VEGFR-3 signaling during inflammatory lymphangiogenesis.

PubMed

Jones, Dennis; Li, Yonghao; He, Yun; Xu, Zhe; Chen, Hong; Min, Wang

2012-03-01

Vascular endothelial growth factor receptor(VEGFR)-3 is a critical regulator of developmental and adult vasculogenesis and lymphangiogenesis through its interactions with select members of the VEGF family. The goal of this study was to investigate how VEGFR-3 expression is regulated during inflammatory lymphangiogenesis. In this study, we present for the first time evidence that VEGFR-3 can be negatively regulated by a mirtron, hsa-miR-1236 (miR-1236), which is expressed in primary human lymphatic endothelial cells. In human lymphatic endothelial cells, miR-1236 is upregulated in response to IL-1β, a negative regulator of VEGFR-3. miR-1236 binds the 3' untranslated region of Vegfr3, resulting in translational inhibition. Overexpression of miR-1236 significantly decreased expression of VEGFR-3, but not VEGFR-2, in human lymphatic endothelial cells. Compared to a control miR, overexpression of miR-1236 also led to decreased VEGFR-3 signaling. However, VEGFR-2-specific signaling was not affected. miR-1236 can attenuate human lymphatic endothelial cell migration and tube formation, as well as in vivo lymphangiogenesis. Our data suggest that miR-1236 may function as a negative regulator of VEGFR-3 signaling during inflammatory lymphangiogenesis.

Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4.

PubMed

Qiu, Zhijuan; Cervantes, Jorge L; Cicek, Basak B; Mukherjee, Subhajit; Venkatesh, Madhukumar; Maher, Leigh A; Salazar, Juan C; Mani, Sridhar; Khanna, Kamal M

2016-08-23

The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr(-/-) mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr(-/-) mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr(-/-) mice. Mechanistically, the heightened inflammation in Pxr(-/-) mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

IL-10 plays a pivotal role in anti-inflammatory effects of resveratrol in activated microglia cells.

PubMed

Cianciulli, Antonia; Dragone, Teresa; Calvello, Rosa; Porro, Chiara; Trotta, Teresa; Lofrumento, Dario Domenico; Panaro, Maria Antonietta

2015-02-01

The development of agents that can modulate microglial activation has been suggested as one potential strategy for the treatment or prevention of neurodegenerative diseases. Among these agents, resveratrol, with its anti-inflammatory action, has been described to have neuroprotective effects. In this paper we demonstrate that in LPS-stimulated microglia resveratrol pretreatment reduced, in a dose-dependent manner, pro-inflammatory cytokines IL-1β, TNF-α and IL-6 mRNA expression and increased the release of anti-inflammatory interleukin (IL)-10. Moreover, resveratrol pretreatment up-regulated the phosphorylated forms of JAK1 and STAT3, as well as suppressor of cytokine signaling (SOCS)3 protein expression in LPS activated cells, demonstrating that the JAK-STAT signaling pathway is involved in the anti-inflammatory effect exerted by resveratrol. By supplementing the cultures with an IL-10 neutralizing antibody (IL-10NA) we obtained the opposite effect. Taken together, these data allow us to conclude that the LPS-induced pro-inflammatory response in microglial cells can be markedly reduced by resveratrol, through IL-10 dependent up-regulation of SOCS3, requiring the JAK-STAT signaling pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination.

PubMed

Defaux, Antoinette; Zurich, Marie-Gabrielle; Braissant, Olivier; Honegger, Paul; Monnet-Tschudi, Florianne

2009-05-07

Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

PubMed Central

Defaux, Antoinette; Zurich, Marie-Gabrielle; Braissant, Olivier; Honegger, Paul; Monnet-Tschudi, Florianne

2009-01-01

Background Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS. Methods Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. Results GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. Conclusion Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-β agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes. PMID:19422681

Rheostat regulation of integrin-mediated leukocyte adhesion

PubMed Central

Douglas, Ivor S.; Dassopoulos, Themistocles

2007-01-01

The homing of activated T lymphocytes to the gut in inflammatory bowel diseases is dependent on their coordinated, integrin-mediated adhesion and de-adhesion to substrates and blood vessel walls. In this issue of the JCI, Park and colleagues reveal a key modulatory role of a binding site within β integrins, known as the ADMIDAS domain, in controlling integrin de-adhesion in mice (see the related article beginning on page 2526). These observations add to our growing understanding of how integrin adhesiveness is regulated and raise the notion of the existence of a biological rheostat for lymphocyte homing. Disturbed migratory rheostat tone could account for variations in interindividual immune responses observed in patients with inflammatory bowel disease or other lymphocyte-mediated inflammatory disorders. These findings will inform future strategies to design small molecules for the treatment of a spectrum of chronic inflammatory conditions. PMID:17786236

Mitochondrial respiration controls lysosomal function during inflammatory T cell responses

PubMed Central

Baixauli, Francesc; Acín-Pérez, Rebeca; Villarroya-Beltrí, Carolina; Mazzeo, Carla; Nuñez-Andrade, Norman; Gabandé-Rodriguez, Enrique; Dolores Ledesma, Maria; Blázquez, Alberto; Martin, Miguel Angel; Falcón-Pérez, Juan Manuel; Redondo, Juan Miguel; Enríquez, Jose Antonio; Mittelbrunn, Maria

2016-01-01

Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration-deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward pro-inflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify novel strategies for intervention in mitochondrial-related diseases. PMID:26299452

Anti-inflammatory effects of eugenol on lipopolysaccharide-induced inflammatory reaction in acute lung injury via regulating inflammation and redox status.

PubMed

Huang, Xianfeng; Liu, Yuanyuan; Lu, Yingxun; Ma, Chunhua

2015-05-01

Acute lung injury (ALI) represents a clinical syndrome that results from complex responses of the lung to a multitude of direct and indirect insults. This study aims to evaluate the possible mechanisms responsible for the anti-inflammatory effects of eugenol (EUL) on lipopolysaccharide (LPS)-induced inflammatory reaction in ALI. ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and EUL (5, and 10 mg/kg) was injected intraperitoneally 1h prior to LPS administration. After 6h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings suggest that the protective mechanism of EUL may be attributed partly to decreased production of proinflammatory cytokines through the regulating inflammation and redox status. The results support that use of EUL is beneficial in the treatment of ALI. Copyright © 2015 Elsevier B.V. All rights reserved.

Blocking NF-κB: an inflammatory issue.

PubMed

Rahman, Arshad; Fazal, Fabeha

2011-11-01

The nuclear factor (NF)-κB is considered the master regulator of inflammatory responses. Studies in mouse models have established this transcription factor as an important mediator of many inflammatory disease states, including pulmonary diseases such as acute lung injury and acute respiratory distress syndrome. Endothelial cells provide the first barrier for leukocytes migrating to the inflamed sites and hence offer an attractive cellular context for targeting NF-κB for treatment of these diseases. However, recent studies showing that NF-κB also plays an important role in resolution phase of inflammation and in tissue repair and homeostasis have challenged the view of therapeutic inhibition of NF-κB. This article reviews the regulation of NF-κB in the context of endothelial cell signaling and provides a perspective on why "dampening" rather than "abolishing" NF-κB activation may be a safe and effective treatment strategy for inflammation-associated pulmonary and other inflammatory diseases.

Bridging the Gaps: the Promise of Omics Studies in Pediatric Exercise Research

PubMed Central

Radom-Aizik, Shlomit; Cooper, Dan M.

2018-01-01

In this review, we highlight promising new discoveries that may generate useful and clinically relevant insights into the mechanisms that link exercise with growth during critical periods of development. Growth in childhood and adolescence is unique among mammals, and is a dynamic process regulated by an evolution of hormonal and inflammatory mediators, age-dependent progression of gene expression, and environmentally modulated epigenetic mechanisms. Many of these same processes likely affect molecular transducers of physical activity. How the molecular signaling associated with growth is synchronized with signaling associated with exercise is poorly understood. Recent advances in “omics,” namely, genomics and epigenetics, metabolomics, and proteomics, now provide exciting approaches and tools that can be used for the first time to address this gap. A biologic definition of “healthy” exercise that links the metabolic transducers of physical activity with parallel processes that regulate growth will transform health policy and guidelines that promote optimal use of physical activity. PMID:27137166

The role of nutraceuticals in anti-aging medicine.

PubMed

Vranesić-Bender, Darija

2010-12-01

'Nutraceuticals' is a wide term including all kinds of food with health or medical effect. Regulations in the world on functional food and nutraceuticals are developed along with the development of new products. This nomenclature is not aligned across legal regulations in different countries. There are several theories trying to interpret the phenomenon of aging and the most interesting theory in terms of nutrition is free radical theory and the possible role of antioxidants in aging process. A large group of substances including vitamins, carotenoids, flavonoids and minerals have in vitro or in vivo clinically significant antioxidant characteristics. There is great interest in anti-aging substances derived from food, and the most popular ingredients are antioxidants, especially coenzyme Q10, phytoestrogens, probiotics and omega-3 fatty acids. These substances have beneficial effect on digestive and immune systems, and modulate inflammatory and degenerative processes in the body. The challenge in the future will be strategic combining of cosmeceuticals and nutraceuticals in order to intervene in biological aging processes and degenerative skin changes.

Molecular Profiling of Multiple Human Cancers Defines an Inflammatory Cancer-Associated Molecular Pattern and Uncovers KPNA2 as a Uniform Poor Prognostic Cancer Marker

PubMed Central

Rachidi, Saleh M.; Qin, Tingting; Sun, Shaoli; Zheng, W. Jim; Li, Zihai

2013-01-01

Background Immune evasion is one of the recognized hallmarks of cancer. Inflammatory responses to cancer can also contribute directly to oncogenesis. Since the immune system is hardwired to protect the host, there is a possibility that cancers, regardless of their histological origins, endow themselves with a common and shared inflammatory cancer-associated molecular pattern (iCAMP) to promote oncoinflammation. However, the definition of iCAMP has not been conceptually and experimentally investigated. Methods and Findings Genome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens from 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. A total of 96 inflammatory genes with consistent dysregulation were identified, including 44 up-regulated and 52 down-regulated genes. Protein expression was confirmed by immunohistochemistry for some of these genes. The iCAMP contains proteins whose roles in cancer have been implicated and others which are yet to be appreciated. The clinical significance of many iCAMP genes was confirmed in multiple independent cohorts of colon and ovarian cancer patients. In both cases, better prognosis correlated strongly with high CXCL13 and low level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An “Inflammatory Gene Integrated Score” was further developed from the combination of 18 iCAMP genes in ovarian cancer, which predicted overall survival. Noticeably, as a selective nuclear import protein whose immuno-regulatory function just begins to emerge, karyopherin alpha 2 (KPNA2) is uniformly up-regulated across cancer types. For the first time, the cancer-specific up-regulation of KPNA2 and its clinical significance were verified by tissue microarray analysis in colon and head-neck cancers. Conclusion This work defines an inflammatory signature shared by seven epithelial cancer types and KPNA2 as a consistently up-regulated protein in cancer. Identification of iCAMP may not only serve as a novel biomarker for prognostication and individualized treatment of cancer, but also have significant biological implications. PMID:23536776

Glycogen synthase kinase-3β (GSK3β) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice

PubMed Central

Zhang, Ping; Katz, Jenny; Michalek, Suzanne M.

2011-01-01

Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia. PMID:18929413

Multi-Drug Resistance Transporter 2 Regulates Mucosal Inflammation by Facilitating the Synthesis of Hepoxilin A3

PubMed Central

Pazos, Michael; Siccardi, Dario; Mumy, Karen L.; Bien, Jeffrey D.; Louie, Steve; Shi, Hai Ning; Gronert, Karsten; Mrsny, Randall J.; McCormick, Beth A.

2008-01-01

Neutrophil transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Thus, insight into the directional movement of neutrophils across epithelial barriers will provide important information relating to the mechanisms of such inflammatory disorders. The eicosanoid hepoxilin A3, an endogenous product of 12-lipoxygenase activity, is secreted from the apical surface of the epithelial barrier and establishes a chemotatic gradient to guide neutrophils from the submucosa, across epithelia to the luminal site of an inflammatory stimulus - the final step in neutrophil recruitment. Currently, little is known regarding how hepoxilin A3 is secreted from the intestinal epithelium during an inflammatory insult. In this study we reveal that hepoxilin A3 is a substrate for the apical efflux ABC transporter, multi-drug resistance protein 2 (MRP2). Moreover, using multiple in vitro and in vivo models we show that induction of intestinal inflammation profoundly up-regulates apical expression of MRP2, and that interfering with hepoxilin A3 synthesis and/or inhibition of MRP2 function results in a marked reduction in inflammation and severity of disease. Lastly, examination of inflamed intestinal epithelia in human biopsies revealed up-regulation of MRP2. Thus, blocking hepoxilin A3 synthesis and/or inhibiting MRP2 may lead to the development of new therapeutic strategies for the treatment of epithelial-associated inflammatory conditions. PMID:19017997

The Pro-inflammatory Effects of Glucocorticoids in the Brain

PubMed Central

Duque, Erica de Almeida; Munhoz, Carolina Demarchi

2016-01-01

Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

Regulatory B cells in human inflammatory and autoimmune diseases: from mouse models to clinical research.

PubMed

Miyagaki, Tomomitsu; Fujimoto, Manabu; Sato, Shinichi

2015-10-01

B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause inflammatory and autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of inflammatory and autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human inflammatory and autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in animal models of inflammatory and autoimmune diseases and in clinical research using human samples. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effects of inhalational anaesthetics in experimental allergic asthma.

PubMed

Burburan, S M; Silva, J D; Abreu, S C; Samary, C S; Guimarães, I H L; Xisto, D G; Morales, M M; Rocco, P R M

2014-06-01

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty-six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro-inflammatory (tumour necrosis factor-α), pro-fibrogenic (transforming growth factor-β) and pro-angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid-2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor-α, transforming growth factor-β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid-2-related factor 2 expression. Sevoflurane down-regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant-antioxidant imbalance, improving lung function in this model of asthma. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

Toll-like receptor signaling in cell proliferation and survival

PubMed Central

Li, Xinyan; Jiang, Song; Tapping, Richard I.

2009-01-01

Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation. PMID:19775907

The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.

PubMed

Moriwaki, Kenta; Balaji, Sakthi; McQuade, Thomas; Malhotra, Nidhi; Kang, Joonsoo; Chan, Francis Ka-Ming

2014-10-16

Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor-interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation by regulating cytokine expression in dendritic cells (DCs). Ripk3(-/-) bone-marrow-derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NF-κB subunit RelB and p50 activation and by impaired caspase 1-mediated processing of interleukin-1β (IL-1β). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3(-/-) mice exhibited an impaired axis of injury-induced IL-1β, IL-23, and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wild-type DCs, but not Ripk3(-/-) DCs. These results reveal an unexpected function of RIPK3 in NF-κB activation, DC biology, innate inflammatory-cytokine expression, and injury-induced tissue repair.

Molecular targets and anti-cancer potential of escin.

PubMed

Cheong, Dorothy H J; Arfuso, Frank; Sethi, Gautam; Wang, Lingzhi; Hui, Kam Man; Kumar, Alan Prem; Tran, Thai

2018-05-28

Escin is a mixture of triterpenoid saponins extracted from the horse chestnut tree, Aesculus hippocastanum. Its potent anti-inflammatory and anti-odematous properties makes it a choice of therapy against chronic venous insufficiency and odema. More recently, escin is being actively investigated for its potential activity against diverse cancers. It exhibits anti-cancer effects in many cancer cell models including lung adenocarcinoma, hepatocellular carcinoma and leukemia. Escin also attenuates tumor growth and metastases in various in vivo models. Importantly, escin augments the effects of existing chemotherapeutic drugs, thereby supporting the role of escin as an adjunct or alternative anti-cancer therapy. The beneficial effects of escin can be attributed to its inhibition of proliferation and induction of cell cycle arrest. By regulating transcription factors/growth factors mediated oncogenic pathways, escin also potentially mitigates chronic inflammatory processes that are linked to cancer survival and resistance. This review provides a comprehensive overview of the current knowledge of escin and its potential as an anti-cancer therapy through its anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Inflammatory and bone turnover markers in relation to PTH and vitamin D status among saudi postmenopausal women with and without osteoporosis

PubMed Central

Al-Daghri, Nasser M; Yakout, Sobhy; Al-Shehri, Eman; Al-Fawaz, Hanan A; Aljohani, Naji; Al-Saleh, Yousef

2014-01-01

Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged around 50 years. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women. PMID:25419393

Inflammatory and bone turnover markers in relation to PTH and vitamin D status among Saudi postmenopausal women with and without osteoporosis

PubMed Central

Al-Daghri, Nasser M; Yakout, Sobhy; Al-Shehri, Eman; Al-Fawaz, Hanan; Aljohani, Naji; Al-Saleh, Yousef

2014-01-01

Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged 50 years and above. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women. PMID:25356143

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw; Liou, Saou-Hsing; Yeh, Szu-Ching

Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs inmore » the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause ICAM-1/IL‑8 expression in endothelial cells via TLRs. • Nickel induces the inflammatory responses via a TLR-4/NF-κB pathway. • Zinc causes the inflammatory responses via a broader TLRs/NF-κB signaling. • Nickel shows a significantly higher inflammatory effect than zinc. • NF-κB activation is the primary mechanism involved in the inflammatory responses.« less

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

PubMed Central

Downey, Luke A.; Loftis, Jennifer M.

2014-01-01

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

Structural analysis of a Petri net model of oxidative stress in atherosclerosis.

PubMed

Kozak, Adam; Formanowicz, Dorota; Formanowicz, Piotr

2018-06-01

Atherosclerosis is a complex process of gathering sub-endothelial plaques decreasing lumen of the blood vessels. This disorder affects people of all ages, but its progression is asymptomatic for many years. It is regulated by many typical and atypical factors including the immune system response, a chronic kidney disease, a diet rich in lipids, a local inflammatory process and a local oxidative stress that is here one of the key factors. In this study, a Petri net model of atherosclerosis regulation is presented. This model includes also some information about stoichiometric relationships between its components and covers all mentioned factors. For the model, a structural analysis based on invariants was made and biological conclusions are presented. Since the model contains inhibitor arcs, a heuristic method for analysis of such cases is presented. This method can be used to extend the concept of feasible t -invariants.

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine.

PubMed

Downey, Luke A; Loftis, Jennifer M

2014-03-15

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes - increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. Published by Elsevier B.V.

Expression of protease-activated receptor (PAR)-2, but not other PARs, is regulated by inflammatory cytokines in rat astrocytes.

PubMed

Sokolova, Elena; Aleshin, Stepan; Reiser, Georg

2012-02-01

Protease-activated receptors (PARs) are widely expressed in the central nervous system (CNS) and are believed to play an important role in normal brain functioning as well as in development of various inflammatory and neurodegenerative disorders. Pathological conditions cause altered expression of PARs in brain cells and therefore altered responsiveness to PAR activation. The exact mechanisms of regulation of PAR expression are not well studied. Here, we evaluated in rat astrocytes the influence of LPS, pro-inflammatory cytokines TNFα and IL-1β and continuous PAR activation by PAR agonists on the expression levels of PARs. These stimuli are important in inflammatory and neurological disorders, where their levels are increased. We report that LPS as well as cytokines TNFα and IL-1β affected only the PAR-2 level, but their effects were opposite. LPS and TNFα increased the functional expression of PAR-2, whereas IL-1β down-regulated the functional response of PAR-2. Agonists of PAR-1 specifically increased mRNA level of PAR-2, but not protein level. Transcript levels of other PARs were not changed after PAR-1 activation. Stimulation of the cells with PAR-2 or PAR-4 agonists did not alter PAR levels. We found that up-regulation of PAR-2 is dependent on PKC activity, mostly via its Ca²⁺-sensitive isoforms. Two transcription factors, NFκB and AP-1, are involved in up-regulation of PAR-2. These findings provide new information about the regulation of expression of PAR subtypes in brain cells. This is of importance for targeting PARs, especially PAR-2, for the treatment of CNS disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

UP-REGULATION OF IL-6, IL-8 AND CCL2 GENE EXPRESSION AFTER ACUTE INFLAMMATION: CORRELATION TO CLINICAL PAIN

PubMed Central

Wang, Xiao-Min; Hamza, May; Wu, Tai-Xia; Dionne, Raymond A.

2012-01-01

Tissue injury initiates a cascade of inflammatory mediators and hyperalgesic substances including prostaglandins, cytokines and chemokines. Using microarray and qRT-PCR gene expression analyses, the present study evaluated changes in gene expression of a cascade of cytokines following acute inflammation and the correlation between the changes in the gene expression level and pain intensity in the oral surgery clinical model of acute inflammation. Tissue injury resulted in a significant up-regulation in the gene expression of Interleukin-6 (IL-6; 63.3-fold), IL-8 (8.1-fold), chemokine (C-C motif) ligand 2 (CCL2; 8.9-fold), chemokine (C-X-C motif) ligand 1 (CXCL1; 30.5-fold), chemokine (C-X-C motif) ligand 2 (CXCL2; 26-fold) and annexin A1 (ANXA1; 12-fold). The up-regulation of IL-6 gene expression was significantly correlated to the up-regulation on the gene expression of IL-8, CCL2, CXCL1 and CXCL2. Interestingly, the tissue injury induced up-regulation of IL-6 gene expression, IL-8 and CCL2 were positively correlated to pain intensity at 3 hours post-surgery, the onset of acute inflammatory pain. However, ketorolac treatment did not have a significant effect on the gene expression of IL-6, IL-8, CCL2, CXCL2 and ANXA1 at the same time point of acute inflammation. These results demonstrate that up-regulation of IL-6, IL-8 and CCL2 gene expression contributes to the development of acute inflammation and inflammatory pain. The lack of effect for ketorolac on the expression of these gene products may be related to the ceiling analgesic effects of non-steroidal anti-inflammatory drugs. PMID:19233564

Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes.

PubMed

Silva-Abreu, Marcelle; Espinoza, Lupe Carolina; Rodríguez-Lagunas, María José; Fábrega, María-José; Espina, Marta; García, María Luisa; Calpena, Ana Cristina

2017-11-28

Rosacea is the most common inflammatory skin disease. It is characterized by erythema, inflammatory papules and pustules, visible blood vessels, and telangiectasia. The current treatment has limitations and unsatisfactory results. Pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptors (PPARs), a nuclear receptor that regulates important cellular functions, including inflammatory responses. The purpose of this study was to evaluate the permeation of PGZ with a selection of penetration enhancers and to analyze its effectiveness for treating rosacea. The high-performance liquid chromatography (HPLC) method was validated for the quantitative determination of PGZ. Ex vivo permeation experiments were realized in Franz diffusion cells using human skin, in which PGZ with different penetration enhancers were assayed. The results showed that the limonene was the most effective penetration enhancer that promotes the permeation of PGZ through the skin. The cytotoxicity studies and the Draize test detected cell viability and the absence of skin irritation, respectively. The determination of the skin color using a skin colorimetric probe and the results of histopathological studies confirmed the ability of PGZ-limonene to reduce erythema and vasodilation. This study suggests new pharmacological indications of PGZ and its possible application in the treatment of skin diseases, namely rosacea.

The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release.

PubMed

Adesso, Simona; Autore, Giuseppina; Quaroni, Andrea; Popolo, Ada; Severino, Lorella; Marzocco, Stefania

2017-12-11

Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV) and deoxynivalenol (DON) are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS) plus Interferon-γ (IFN) in the non-tumorigenic intestinal epithelial cell line (IEC-6). The inflammatory response induced by NIV and DON involves tumor necrosis factor-α (TNF-α) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, nitrotyrosine formation, reactive oxygen species (ROS) release, Nuclear Factor-κB (NF-κB), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro-inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern.

Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases.

PubMed

Cutolo, Maurizio; Paolino, Sabrina; Pizzorni, Carmen

2014-01-01

Several chronic inflammatory conditions and autoimmune diseases involving different organs and tissues have been found at risk of progression to cancer. A wide array of proinflammatory cytokines, prostaglandins, nitric oxide products, and matricellular proteins are closely involved in premalignant and malignant transition of cells almost always in a background of chronic inflammation. Interestingly, epigenetic perturbations (i.e. miRNA aberrations, altered DNA methylation) together with important steroid hormone metabolic changes (i.e. oestrogens), or the altered vitamin D concentrations that may unbalance the immune / inflammatory response, have been found linked to the risk and severity in several chronic inflammatory conditions, as well as in cancer. In particular, it is evident, that not only the parent oestrogen but also oestrogen metabolites should be taken into account when this process is evaluated, specially the formation of catecholoestrogen metabolites, that are capable of forming either stable or depurinating DNA adducts, which can cause extensive DNA damage. It is interesting that today the successful treatment of several chronic immune/inflammatory rheumatic diseases is obtained also by using medications initially developed for their use in oncology. The circadian increase of growth factors, specially during the late night, in both chronic inflammation and in cancer patients, as well as the presence of oestrogen-regulated circadian mechanisms, suggests further important links.

Gamma Delta T-Cells Regulate Inflammatory Cell Infiltration of the Lung after Trauma-Hemorrhage

DTIC Science & Technology

2015-06-01

suggesting a role for this T- cell subset in both innate and acquired immunity (7, 8). Studies have shown that +% T cells are required for both controlled...increased infiltration of both lymphoid and myeloid cells in WT mice after TH-induced ALI. In parallel to +% T cells , myeloid cells (i.e., monocytes...GAMMA DELTA T CELLS REGULATE INFLAMMATORY CELL INFILTRATION OF THE LUNG AFTER TRAUMA-HEMORRHAGE Meenakshi Rani,* Qiong Zhang,* Richard F. Oppeltz

Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance.

PubMed

Lee, Byung-Cheol; Lee, Jongsoon

2014-03-01

There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Copyright © 2013 Elsevier B.V. All rights reserved.

MiR-338-5p Promotes Inflammatory Response of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Targeting SPRY1.

PubMed

Yang, Yan; Wang, Yanfeng; Liang, Qingwei; Yao, Lutian; Gu, Shizhong; Bai, Xizhuang

2017-08-01

Our purpose is to study the roles of microRNA-338-5p (miR-338-5p) on the proliferation, invasion, and inflammatory response of fibroblast-like synoviocytes (SFs) in rheumatoid arthritis patients by regulating SPRY1. The target relationship between miR-338-5p and SPRY1 was validated through luciferase reporter system. The expression of miR-338-5p and SPRY1 in synovial tissues and synovial cells were detected using RT-PCR and western blot. The mimics and inhibitors of miR-338-5p were transfected into SFs. MTT, Transwell, and ELISA assays were used to analyze cell proliferation, invasiveness, and the secreted extracellular pro-inflammatory cytokines (such as IL-1a, IL-6, COX2) levels of SFs. MiR-338-5p was highly expressed in rheumatoid arthritis tissues and cells, and directly down-regulated the expression of SPRY1 in the SFs of rheumatoid arthritis patients. Cell proliferation, invasiveness and the expression level of pro-inflammatory cytokines in synovial cells increased after the transfection of miR-338-5p mimics, while the proliferation, invasion and expression level of pro-inflammatory cytokines decreased after the transfection of miR-338-5p inhibitors. In conclusion,miR-338-5p promoted the proliferation, invasion and inflammatory reaction in SFs of rheumatoid arthritis by directly down-regulating SPRY1 expression. J. Cell. Biochem. 118: 2295-2301, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Applications of Genetically Modified Immunobiotics with High Immunoregulatory Capacity for Treatment of Inflammatory Bowel Diseases.

PubMed

Shigemori, Suguru; Shimosato, Takeshi

2017-01-01

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic inflammatory diseases characterized by dysregulated immune responses of the gastrointestinal tract. In recent years, the incidence of IBDs has increased in developed nations, but their prophylaxis/treatment is not yet established. Site-directed delivery of molecules showing anti-inflammatory properties using genetically modified (gm)-probiotics shows promise as a new strategy for the prevention and treatment of IBD. Advantages of gm-probiotics include (1) the ability to use bacteria as a delivery vehicle, enabling safe and long-term use by humans, (2) decreased risks of side effects, and (3) reduced costs. The intestinal delivery of anti-inflammatory proteins such as cytokines and enzymes using Lactococcus lactis has been shown to regulate host intestinal homeostasis depending on the delivered protein-specific machinery. Additionally, clinical experience using interleukin 10-secreting Lc. lactis has been shown to be safe and to facilitate biological containment in IBD therapy. On the other hand, some preclinical studies have demonstrated that gm-strains of immunobiotics (probiotic strains able to beneficially regulate the mucosal immunity) provide beneficial effects on intestinal inflammation as a result of the synergy between the immunoregulatory effects of the bacterium itself and the anti-inflammatory effects of the delivered recombinant proteins. In this review, we discuss the rapid progression in the development of strategies for the prophylaxis and treatment of IBD using gm-probiotics that exhibit immune regulation effects (gm-immunobiotics). In particular, we discuss the type of strains used as delivery agents.

Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP

PubMed Central

Parsa, Kishore V. L; Ganesan, Latha P; Rajaram, Murugesan V. S; Gavrilin, Mikhail A; Balagopal, Ashwin; Mohapatra, Nrusingh P; Wewers, Mark D; Schlesinger, Larry S; Gunn, John S; Tridandapani, Susheela

2006-01-01

Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida–induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida–induced cytokine production through the inhibition of NFκB. Consistently, macrophages lacking SHIP displayed enhanced NFκB-driven gene transcription, whereas overexpression of SHIP led to decreased NFκB activation. Thus, we propose that SHIP negatively regulates F. novicida–induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFκB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia. PMID:16848641

DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes.

PubMed

Habibian, Justine S; Jefic, Mitra; Bagchi, Rushita A; Lane, Robert H; McKnight, Robert A; McKinsey, Timothy A; Morrison, Ron F; Ferguson, Bradley S

2017-10-10

Adipose tissue inflammation is a central pathological element that regulates obesity-mediated insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal-regulated kinase (ERK 1/2) activation (i.e. phosphorylation) links tumor necrosis factor α (TNFα) to pro-inflammatory gene expression in the nucleus. Dual specificity phosphatases (DUSPs) inactivate ERK 1/2 through dephosphorylation and can thus inhibit inflammatory gene expression. We report that DUSP5, an ERK1/2 phosphatase, was induced in epididymal white adipose tissue (WAT) in response to diet-induced obesity. Moreover, DUSP5 mRNA expression increased during obesity development concomitant to increases in TNFα expression. Consistent with in vivo findings, DUSP5 mRNA expression increased in adipocytes in response to TNFα, parallel with ERK1/2 dephosphorylation. Genetic loss of DUSP5 exacerbated TNFα-mediated ERK 1/2 signaling in 3T3-L1 adipocytes and in adipose tissue of mice. Furthermore, inhibition of ERK 1/2 and c-Jun N terminal kinase (JNK) signaling attenuated TNFα-induced DUSP5 expression. These data suggest that DUSP5 functions in the feedback inhibition of ERK1/2 signaling in response to TNFα, which resulted in increased inflammatory gene expression. Thus, DUSP5 potentially acts as an endogenous regulator of adipose tissue inflammation; although its role in obesity-mediated inflammation and insulin signaling remains unclear.

Growth promotion in pigs by oxytetracycline coincides with down regulation of serum inflammatory parameters and of hibernation-associated protein HP-27.

PubMed

Soler, Laura; Miller, Ingrid; Hummel, Karin; Razzazi-Fazeli, Ebrahim; Jessen, Flemming; Escribano, Damian; Niewold, Theo

2016-05-01

The growth promoting effect of supplementing animal feed with antibiotics like tetracycline has traditionally been attributed to their antibiotic character. However, more evidence has been accumulated on their direct anti-inflammatory effect during the last two decades. Here we used a pig model to explore the systemic molecular effect of feed supplementation with sub therapeutic levels of oxytetracycline (OTC) by analysis of serum proteome changes. Results showed that OTC promoted growth, coinciding with a significant down regulation of different serum proteins related to inflammation, oxidation and lipid metabolism, confirming the anti-inflammatory mechanism of OTC. Interestingly, apart from the classic acute phase reactants also down regulation was seen of a hibernation associated plasma protein (HP-27), which is to our knowledge the first description in pigs. Although the exact function in non-hibernators is unclear, down regulation of HP-27 could be consistent with increased appetite, which is possibly linked to the anti-inflammatory action of OTC. Given that pigs are good models for human medicine due to their genetic and physiologic resemblance, the present results might also be used for rational intervention in human diseases in which inflammation plays an important role such as obesity, type 2 diabetes and cardiovascular diseases. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Immunological function of vitamin D during human pregnancy.

PubMed

Ji, Jin-Lu; Muyayalo, Kahinho P; Zhang, Yong-Hong; Hu, Xiao-Hui; Liao, Ai-Hua

2017-08-01

The well-established classic role of vitamin D is implicated in the regulation of the balance between calcium and phosphorus. Furthermore, vitamin D is also involved in many non-classic physiological processes, mainly including the regulation of cell proliferation, differentiation, apoptosis and immune function, participation in the inflammatory response and maintenance of genome stability function. During pregnancy, vitamin D receptor and its metabolic enzymes are expressed at the placenta and decidua, indicating the potential role in the mechanism of immunomodulation at the maternal-fetal interface. The insufficiency or deficiency of vitamin D may affect the mother directly and is related to specific pregnancy outcomes, such as preeclampsia, gestational diabetes, and recurrent miscarriage. This article reviews the effects of vitamin D on immune regulation during pregnancy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients.

PubMed

Chacón, Pedro; Vega, Antonio; Monteseirín, Javier; El Bekay, Rajaa; Alba, Gonzalo; Pérez-Formoso, José Luis; Msartínez, Alberto; Asturias, Juan A; Pérez-Cano, Ramón; Sobrino, Francisco; Conde, José

2005-08-01

Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of COX-2 expression is responsible for increased PG release during inflammatory conditions and is thought to be also involved in allergic states. In this study, we demonstrate that in human T, B and natural killer lymphocytes from allergic patients, COX-2 expression became induced upon cell challenge with specific allergens and that this process is presumably IgE dependent and occurs after CD23 receptor ligation. This induction took place at both mRNA and protein levels and was accompanied by PGD2 release. IgE-dependent lymphocyte treatment elicited, in parallel, an activation of the MAPK p38 and extracellular signal-regulated kinase 1/2, an enhancement of calcineurin (CaN) activity, and an increase of the DNA-binding activity of the nuclear factor of activated T cells and of NF-kappaB, with a concomitant decrease in the levels of the cytosolic inhibitor of kappaB, IkappaB. In addition, specific chemical inhibitors of MAPK, such as PD098059 and SB203580, as well as MG-132, an inhibitor of proteasomal activity, abolished allergen-induced COX-2 up-regulation, suggesting that this process is mediated by MAPK and NF-kappaB. However, induction of COX-2 expression was not hampered by the CaN inhibitor cyclosporin A. We also examined the effect of a selective COX-2 inhibitor, NS-398, on cytokine production by human lymphocytes. Treatment with NS-398 severely diminished the IgE-dependently induced production of IL-8 and TNF-alpha. These results underscore the relevant role of lymphocyte COX-2 in allergy and suggest that COX-2 inhibitors may contribute to the improvement of allergic inflammation through the reduction of inflammatory mediator production by human lymphocytes.

Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verret, Valentin, E-mail: valentin.verret@archimmed.com; Namur, Julien; Ghegediban, Saieda Homayra

The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 andmore » 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.« less

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach

PubMed Central

You, Sungyong; Yoo, Seung-Ah; Choi, Susanna; Kim, Ji-Young; Park, Su-Jung; Ji, Jong Dae; Kim, Tae-Hwan; Kim, Ki-Jo; Cho, Chul-Soo; Hwang, Daehee; Kim, Wan-Uk

2014-01-01

Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)–stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS–dominant (invasive), and RA-SM–dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix–loop–helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. PMID:24374632

Dual Effects of Cell Free Supernatants from Lactobacillus acidophilus and Lactobacillus rhamnosus GG in Regulation of MMP-9 by Up-Regulating TIMP-1 and Down-Regulating CD147 in PMA- Differentiated THP-1 Cells

PubMed Central

Maghsood, Faezeh; Mirshafiey, Abbas; Farahani, Mohadese M.; Modarressi, Mohammad Hossein; Jafari, Parvaneh; Motevaseli, Elahe

2018-01-01

Objective Recent studies have reported dysregulated expression of matrix metalloproteinases (MMPs), especially MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1, -2 (TIMP-1, TIMP-2), and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in activated macrophages of patients with inflammatory diseases. Therefore, MMP-2, MMP-9, and their regulators may represent a new target for treatment of inflammatory diseases. Probiotics, which are comprised of lactic acid bacteria, have the potential to modulate inflammatory responses. In this experimental study, we investigated the anti-inflammatory effects of cell-free supernatants (CFS) from Lactobacillus acidophilus (L. acidophilus) and L. rhamnosus GG (LGG) in phorbol myristate acetate (PMA)-differentiated THP-1 cells. Materials and Methods In this experimental study, PMA-differentiated THP-1 cells were treated with CFS from L. acidophilus, LGG and uninoculated bacterial growth media (as a control). The expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNAs were determined using real-time quantitative reverse transcription polymerase chain reaction (RT- PCR). The levels of cellular surface expression of CD147 were assessed by flow cytometry, and the gelatinolytic activity of MMP-2 and MMP-9 were determined by zymography. Results Our results showed that CFS from both L. acidophilus and LGG significantly inhibited the gene expression of MMP-9 (P=0.0011 and P=0.0005, respectively), increased the expression of TIMP-1 (P<0.0001), decreased the cell surface expression of CD147 (P=0.0307 and P=0.0054, respectively), and inhibited the gelatinolytic activity of MMP-9 (P=0.0003 and P<0.0001, respectively) in PMA-differentiated THP-1 cells. Although, MMP-2 expression and activity and TIMP-2 expression remained unchanged. Conclusion Our results indicate that CFS from L. acidophilus and LGG possess anti-inflammatory properties and can modulate the inflammatory response. PMID:29105390

The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory 'M1' human macrophages.

PubMed

Narayan, Nehal; Mandhair, Harpreet; Smyth, Erica; Dakin, Stephanie Georgina; Kiriakidis, Serafim; Wells, Lisa; Owen, David; Sabokbar, Afsie; Taylor, Peter

2017-01-01

The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.

CD14 Signaling Restrains Chronic Inflammation through Induction of p38-MAPK/SOCS-Dependent Tolerance

PubMed Central

Sahay, Bikash; Patsey, Rebeca L.; Eggers, Christian H.; Salazar, Juan C.; Radolf, Justin D.; Sellati, Timothy J.

2009-01-01

Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes. PMID:20011115

Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection.

PubMed

Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang; Mahdi, Rashid M; Shen, De Fen; Chan, Chi-Chao; Egwuagu, Charles E

2015-04-01

Immunological responses to pathogens are stringently regulated in the eye to prevent excessive inflammation that damage ocular tissues and compromise vision. Suppressors of cytokine signaling (SOCS) regulate intensity/duration of inflammatory responses. We have used SOCS1-deficient mice and retina-specific SOCS1 transgenic rats to investigate roles of SOCS1 in ocular herpes simplex virus (HSV-1) infection and non-infectious uveitis. We also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and examined whether they can be used to inhibit inflammatory cytokines. Overexpression of SOCS1 in transgenic rat eyes attenuated ocular HSV-1 infection while SOCS1-deficient mice developed severe non-infectious anterior uveitis, suggesting that SOCS1 may contribute to mechanism of ocular immune privilege by regulating trafficking of inflammatory cells into ocular tissues. Furthermore, MTS-SOCS1 inhibited IFN-γ-induced signal transducers and activators of transcription 1 (STAT1) activation by macrophages while MTS-SOCS3 suppressed expansion of pathogenic Th17 cells that mediate uveitis, indicating that MTS-SOCS proteins maybe used to treat ocular inflammatory diseases of infectious or autoimmune etiology.

Regulation of Inflammatory Pathways in Cancer and Infectious Disease of the Cervix

PubMed Central

Adefuye, Anthonio; Sales, Kurt

2012-01-01

Cervical cancer is one of the leading gynaecological malignancies worldwide. It is an infectious disease of the cervix, associated with human papillomavirus infection (HPV), infection with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoea as well as human immunodeficiency virus (HIV). Furthermore, it is an AIDS-defining disease with an accelerated mortality in HIV-infected women with cervical cancer. With the introduction of robust vaccination strategies against HPV in the developed world, it is anticipated that the incidence of cervical cancer will decrease in the coming years. However, vaccination has limited benefit for women already infected with high-risk HPV, and alternative therapeutic intervention strategies are needed for these women. Many pathological disorders, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways which are considered to be regulated by infectious agents. In cervical cancer, hyperactivation of these inflammatory pathways and regulation of immune infiltrate into tissues can potentially play a role not only in tumorigenesis but also in HIV infection. In this paper we will discuss the contribution of inflammatory pathways to cervical cancer progression and HIV infection and the role of HIV in cervical cancer progression. PMID:24278714

Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1β Production

PubMed Central

2016-01-01

IL-1β is one of the main proinflammatory cytokines that regulates a broad range of immune responses and also participates in several physiological processes. The canonical production of IL-1β requires multiprotein complexes called inflammasomes. One of the most intensively studied inflammasome complexes is the NLRP3 inflammasome. Its activation requires two signals: one signal “primes” the cells and induces the expression of NLRP3 and pro-IL-1β, while the other signal leads to the assembly and activation of the complex. Several stimuli were reported to function as the second signal including reactive oxygen species, lysosomal rupture, or cytosolic ion perturbation. Despite very intensive studies, the precise function and regulation of the NLRP3 inflammasome are still not clear. However, many chronic inflammatory diseases are related to the overproduction of IL-1β that is mediated via the NLRP3 inflammasome. In this review, we aimed to provide an overview of studies that demonstrated the effect of plant-derived natural compounds on NLRP3 inflammasome-mediated IL-1β production. Although many of these studies lack the mechanistic explanation of their action, these compounds may be considered as complementary supplements in the treatment of chronic inflammatory diseases, consumed as preventive agents, and may also be considered as molecular tools to study NLRP3 function. PMID:27672241

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

PubMed

Takyar, Seyedtaghi; Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren; Elias, Jack A

2013-09-23

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis

PubMed Central

Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren

2013-01-01

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma. PMID:24043765

LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis

PubMed Central

Nakamura, Takahiro; Hamuro, Junji; Takaishi, Mikiro; Simmons, Szandor; Maruyama, Kazuichi; Zaffalon, Andrea; Bentley, Adam J.; Kawasaki, Satoshi; Nagata-Takaoka, Maho; Fullwood, Nigel J.; Itami, Satoshi; Sano, Shigetoshi; Ishii, Masaru; Barrandon, Yann; Kinoshita, Shigeru

2013-01-01

Corneal integrity and transparency are indispensable for good vision. Cornea homeostasis is entirely dependent upon corneal stem cells, which are required for complex wound-healing processes that restore corneal integrity following epithelial damage. Here, we found that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is highly expressed in the human holoclone-type corneal epithelial stem cell population and sporadically expressed in the basal cells of ocular-surface epithelium. In murine models, LRIG1 regulated corneal epithelial cell fate during wound repair. Deletion of Lrig1 resulted in impaired stem cell recruitment following injury and promoted a cell-fate switch from transparent epithelium to keratinized skin-like epidermis, which led to corneal blindness. In addition, we determined that LRIG1 is a negative regulator of the STAT3-dependent inflammatory pathway. Inhibition of STAT3 in corneas of Lrig1–/– mice rescued pathological phenotypes and prevented corneal opacity. Additionally, transgenic mice that expressed a constitutively active form of STAT3 in the corneal epithelium had abnormal features, including corneal plaques and neovascularization similar to that found in Lrig1–/– mice. Bone marrow chimera experiments indicated that LRIG1 also coordinates the function of bone marrow–derived inflammatory cells. Together, our data indicate that LRIG1 orchestrates corneal-tissue transparency and cell fate during repair, and identify LRIG1 as a key regulator of tissue homeostasis. PMID:24316976

Platelet-Derived CCL5 Regulates CXC Chemokine Formation and Neutrophil Recruitment in Acute Experimental Colitis.

PubMed

Yu, Changhui; Zhang, Songen; Wang, Yongzhi; Zhang, Su; Luo, Lingtao; Thorlacius, Henrik

2016-02-01

Accumulating data suggest that platelets not only regulate thrombosis and haemostasis but also inflammatory processes. Platelets contain numerous potent pro-inflammatory compounds, including the chemokines CCL5 and CXCL4, although their role in acute colitis remains elusive. The aim of this study is to examine the role of platelets and platelet-derived chemokines in acute colitis. Acute colitis is induced in female Balb/c mice by administration of 5% dextran sodium sulfate (DSS) for 5 days. Animals receive a platelet-depleting, anti-CCL5, anti-CXCL4, or a control antibody prior to DSS challenge. Colonic tissue is collected for quantification of myeloperoxidase (MPO) activity, CXCL5, CXCL2, interleukin-6 (IL-6), and CCL5 levels as well as morphological analyses. Platelet depletion reduce tissue damage and clinical disease activity index in DSS-exposed animals. Platelet depletion not only reduces levels of CXCL2 and CXCL5 but also levels of CCL5 in the inflamed colon. Immunoneutralization of CCL5 but not CXCL4 reduces tissue damage, CXC chemokine expression, and neutrophil recruitment in DSS-treated animals. These findings show that platelets play a key role in acute colitis by regulating CXC chemokine generation, neutrophil infiltration, and tissue damage in the colon. Moreover, our results suggest that platelet-derived CCL5 is an important link between platelet activation and neutrophil recruitment in acute colitis. © 2015 Wiley Periodicals, Inc.

Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

PubMed Central

Knights, Alexander J.; Yik, Jinfen J.; Mat Jusoh, Hanapi; Norton, Laura J.; Funnell, Alister P. W.; Pearson, Richard C. M.; Bell-Anderson, Kim S.; Crossley, Merlin; Quinlan, Kate G. R.

2016-01-01

The Lgals3 gene encodes a multifunctional β-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future. PMID:27226561

Resveratrol reduces senescence-associated secretory phenotype by SIRT1/NF-κB pathway in gut of the annual fish Nothobranchius guentheri.

PubMed

Liu, Shan; Zheng, Zhaodi; Ji, Shuhua; Liu, Tingting; Hou, Yanhan; Li, Shasha; Li, Guorong

2018-06-13

Senescent cells display a senescence-associated secretory phenotype (SASP), which contributes to aging. Resveratrol, an activator of SIRT1, has anti-aging, anti-inflammatory, anti-oxidant, anti-free radical and other pharmacological effects. The genus of the annual fish Nothobranchius has become an emerging animal model for studying aging. However, the underlying mechanism for resveratrol to delay aging by SASP regulation has not been elucidated in vertebrates. In this study, the annual fish N. guentheri were fed with resveratrol for long-term treatment. The results showed that resveratrol reversed intensive senescence-associated β-galactosidase activity with aging process, down-regulated levels of SASP-associated proinflammatory cytokines IL-8 and TNFα, and up-regulated expression of anti-inflammatory cytokine IL-10 in gut of the fish. Resveratrol increased SIRT1 expression, and inhibited NF-κB by decreasing RelA/p65, Ac-RelA/p65 and p-IκBα levels and by increasing the interaction between SIRT1 and RelA/p65. Moreover, resveratrol reversed the decline of intestinal epithelial cells (IECs) and intestinal stem cells (ISCs) caused by aging in gut of the fish. Together, our results implied that resveratrol inhibited SASP through SIRT1/NF-κB signaling pathway and delayed aging of the annual fish N. guentheri. Copyright © 2018. Published by Elsevier Ltd.

Inhibitory Effects of Emodin, Thymol, and Astragalin on Leptospira interrogans-Induced Inflammatory Response in the Uterine and Endometrium Epithelial Cells of Mice.

PubMed

Zhang, Wenlong; Lu, Xiaojie; Wang, Wei; Ding, Zhuang; Fu, Yunhe; Zhou, Xiaofei; Zhang, Naisheng; Cao, Yongguo

2017-04-01

Leptospirosis is a systemic infection that causes, among others, acute kidney injury, acute liver disease, muscle pain, vasculitis, bleeding disorders, and reproductive loss. In an effort to reduce uterine inflammatory responses induced by Leptospira, we evaluated the anti-inflammation effects of emodin, thymol, and astragalin in a mouse model. Our results showed that treatment with emodin, thymol, and astragalin alleviated uterine inflammation induced by leptospira infection via suppression of pro-inflammatory cytokine expression and prevented tissue damage. Furthermore, we used primary endometrium epithelial cells to show that treatment with these chemicals inhibited the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Western blot results showed that these chemicals suppressed the phosphorylation of p38, p65, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. These results indicate that treatment with emodin, thymol, and astragalin suppressed inflammatory response by regulating NF-κB and mitogen-activated protein kinase signaling pathways in leptospira-infected uterine and endometrium epithelial cells of mice.

Toll-like receptor-mediated inhibition of Gas6 and ProS expression facilitates inflammatory cytokine production in mouse macrophages

PubMed Central

Deng, Tingting; Zhang, Yue; Chen, Qiaoyuan; Yan, Keqin; Han, Daishu

2012-01-01

Activation of Toll-like receptors (TLRs) triggers rapid inflammatory cytokine production in various cell types. The exogenous product of growth-arrest-specific gene 6 (Gas6) and Protein S (ProS) inhibit the TLR-triggered inflammatory responses through the activation of Tyro3, Axl and Mer (TAM) receptors. However, regulation of the Gas6/ProS-TAM system remains largely unknown. In the current study, mouse macrophages are shown to constitutively express Gas6 and ProS, which synergistically suppress the basal and TLR-triggered production of inflammatory cytokines, including those of tumour necrosis factor-α, interleukin-6 and interleukin-1β, by the macrophages in an autocrine manner. Notably, TLR signalling markedly decreases Gas6 and ProS expression in macrophages through the activation of the nuclear factor-κB. Further, the down-regulation of Gas6 and ProS by TLR signalling facilitates the TLR-mediated inflammatory cytokine production in mouse macrophages. These results describe a self-regulatory mechanism of TLR signalling through the suppression of Gas6 and ProS expression. PMID:22043818

Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease

PubMed Central

Iyer, Shankar Subramanian; Cheng, Genhong

2012-01-01

Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis. Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases. Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response. In this review, we discuss modes of regulation of IL-10 gene expression in immune effector cell types, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression. PMID:22428854

[Apoptosis: cellular and clinical aspects].

PubMed

Løvschall, H; Mosekilde, L

1997-04-01

Removal of damaged cells is essential for the maintenance of life in multicellular organisms. The process of self destruction, apoptosis, eliminates surplus or damaged cells as part of the pathophysiological defence system. Apoptosis is essential in structural and functional organogenesis during embryological development. The physiological regulation of tissue kinetics is a product of both cell proliferation and cell death. Internal and external regulatory stimuli regulate the balance between apoptosis and mitosis by genetic interaction. Apoptosis is characterized by condensation of chromatine as a result of DNA degradation, formation of blebs in the plasma and nuclear membranes, condensation of cytoplasma, formation of vesicular apoptotic bodies, and phagocytosis by neighbouring cells without inflammatory response. A number of observations indicate that programmed cell death plays an important role in the regulation of cytofunctional homeostasis and defense against accumulation of damaged cells, eg with DNA alterations. Dysregulation of the apoptotic gene program, eg by mutations, may not only lead to loss or degeneration of tissue, but also to hyperproliferative and tumorigenic disorders. New evidence indicates that apoptosis regulation is important both in aging processes and diseases such as: neuropathies, immunopathies, viral infections, cancer, etc. Pharmacological intervention designed to modulate apoptosis seems to raise new possibilities in the treatment of disease.

Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potapovich, Alla I.; Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050; Lulli, Daniela

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure,more » the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights: > Effects of plant polyphenols on inflammatory responses in human keratinocytes. > Inflammatory stimuli used: TGFalpha, TNFalpha+IFNgamma, UVA+UVB, and LPS. > Inflammatory pathways connected with NFB, ERK1/2, EGFR, and AhR were investigated. > Plant polyphenols, flavonoids, stilbenoids, and phenylpropanoids, were studied. > Modulation of inflammation depends on phenolic core structure and glycosylation.« less

G-protein coupled receptor 30 (GPR30): a novel regulator of endothelial inflammation.

PubMed

Chakrabarti, Subhadeep; Davidge, Sandra T

2012-01-01

Estrogen, the female sex hormone, is known to exert anti-inflammatory and anti-atherogenic effects. Traditionally, estrogen effects were believed to be largely mediated through the classical estrogen receptors (ERs). However, there is increasing evidence that G-protein coupled receptor 30 (GPR30), a novel estrogen receptor, can mediate many estrogenic effects on the vasculature. Despite this, the localization and functional significance of GPR30 in the human vascular endothelium remains poorly understood. Given this background, we examined the subcellular location and potential anti-inflammatory roles of GPR30 using human umbilical vein endothelial cells as a model system. Inflammatory changes were induced by treatment with tumor necrosis factor (TNF), a pro-inflammatory cytokine involved in atherogenesis and many other inflammatory conditions. We found that GPR30 was located predominantly in the endothelial cell nuclei. Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was completely abolished by the selective GPR30 antagonist G-15, suggesting that it was indeed mediated in a GPR30 dependent manner. Interestingly, estrogen alone had no effects on TNF-treated endothelium. Concomitant activation of the classical ERs blocked the anti-inflammatory effects of G-1, indicating opposing effects of GPR30 and the classical ERs. Our findings demonstrate that endothelial GPR30 is a novel regulator of the inflammatory response which could be a potential therapeutic target against atherosclerosis and other inflammatory diseases.

Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages.

PubMed

Moore, Sherri M; Holt, Vivian V; Malpass, Lillie R; Hines, Ian N; Wheeler, Michael D

2015-10-01

The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tumor necrosis factor-α suppresses adipogenic and osteogenic differentiation of human periodontal ligament stem cell by inhibiting miR-21/Spry1 functional axis.

PubMed

Yang, Nan; Li, Yang; Wang, Guang; Ding, Yin; Jin, Yan; Xu, Yiquan

Periodontitis is a chronic infectious disease that leads to progressive destruction of periodontal tissue. Human periodontal ligament stem cells (PDLSCs) are the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. PDLSCs derived from inflammatory microenvironment show attenuated differentiation potential, however the mechanism is still unclear. MicroRNAs (miRNAs) are a newly discovered class of posttranscriptional regulators, and they play key roles in regulating cell differentiation. Recent studies have demonstrated that inflammatory cytokines could regulate miRNAs and contribute to some inflammatory diseases. Tumor necrosis factor (TNF-α) is a potent negative regulator of cell differentiation. Elevated levels of TNF-α were confirmed to be associated with the severity of periodontal disease. Here, we found TNF-α inhibited the adipogenic and osteogenic differentiation of PDLSCs. Based on this, we hypothesized that TNF-α could participate in PDLSC differentiation by regulating miRNA signal pathway. Moreover, we demonstrated that the expression of miR-21 was suppressed by TNF-α in impaired adipogenic and osteogenic differentiation of PDLSCs. Upregulating miR-21 can partly rescue TNF-α-impaired adipogenesis and osteogenesis by repressing its target gene Spry1, suggested that miR-21/Spry1 functional axis plays critical role in PDLSC differentiation under inflammatory microenvironment. During adipogenesis and osteogenesis, TNF-α significantly increased Spry1 levels and overexpression of miR-21 dramatically decreased Spry1 levels in the presence of TNF-α, indicated important roles of miR-21 in modulating link between TNF-α and Spry1. Our findings introduce a molecular mechanism in which TNF-α suppresses adipogenic and osteogenic differentiation of PDLSCs by inhibiting miR-21/Spry1 functional axis. This study may indicate a molecular basis for novel therapeutic strategies against periodontitis and other inflammatory diseases. Copyright © 2017. Published by Elsevier B.V.

Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Wei-Xin, E-mail: weixinliu@yahoo.com; Wang, Ting; Zhou, Feng

Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentarymore » group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory response. • Exercise prevents colonic inflammation in obesity by up-regulating PPAR-γ.« less

Cold exposure down-regulates immune response pathways in ferret aortic perivascular adipose tissue.

PubMed

Reynés, Bàrbara; van Schothorst, Evert M; García-Ruiz, Estefanía; Keijer, Jaap; Palou, Andreu; Oliver, Paula

2017-05-03

Perivascular adipose tissue (PVAT) surrounds blood vessels and releases paracrine factors, such as cytokines, which regulate local inflammation. The inflammatory state of PVAT has an important role in vascular disease; a pro-inflammatory state has been related with atherosclerosis development, whereas an anti-inflammatory one is protective. Cold exposure beneficially affects immune responses and, could thus impact the pathogenesis of cardiovascular diseases. In this study, we investigated the effects of one-week of cold exposure at 4°C of ferrets on aortic PVAT (aPVAT) versus subcutaneous adipose tissue. Ferrets were used because of the similarity of their adipose tissues to those of humans. A ferret-specific Agilent microarray was designed to cover the complete ferret genome and global gene expression analysis was performed. The data showed that cold exposure altered gene expression mainly in aPVAT. Most of the regulated genes were associated with cell cycle, immune response and gene expression regulation, and were mainly down-regulated. Regarding the effects on immune response, cold acclimation decreased the expression of genes involved in antigen recognition and presentation, cytokine signalling and immune system maturation and activation. This immunosuppressive gene expression pattern was depot-specific, as it was not observed in the inguinal subcutaneous depot. Interestingly, this depression in immune response related genes was also evident in peripheral blood mononuclear cells (PBMC). In conclusion, these results reveal that cold acclimation produces an inhibition of immune response-related pathways in aPVAT, reflected in PBMC, indicative of an anti-inflammatory response, which can potentially be exploited for the enhancement or maintenance of cardiovascular health.

Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators.

PubMed

Harizi, Hedi; Gualde, Norbert

2006-08-01

Exposure to pathogens induces antigen-presenting cells (APC) such as macrophages and dendritic cells (DC) to produce various endogenous mediators, including arachidonic acid (AA)-derived eicosanoids, cytokines, and nitric oxide (NO). Many secreted products of activated APC can act by themselves in an autocrine manner and modulate their function. Moreover, the cross-interaction between endogenous bioactive molecules regulates the function of professional APC with important consequences for their ability to activate and sustain immune and inflammatory responses, and to regulate immune homeostasis. Although neglected for many years when compared to their role in cardiovascular homeostasis, cancer and inflammation, the importance of eicosanoids in immunology is becoming more defined. The role of prostaglandin (PG) E2 (PGE2), one of the best known and most well studied eicosanoids, is of particular interest. It modulates the activities of professional DC by acting on their differentiation, maturation and their ability to secrete cytokines. Uniquely among haematopoietic cytokines, interleukin-10 (IL-10) is a pleiotropic molecule that displays both immunostimulatory and immunoregulatory activities. IL-10 has attached much attention because of its anti-inflammatory properties. It modulates expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, particularly macrophages and DC. We previously reported that PGE2 is a potent inducer of IL-10 in bone marrow-derived DC (BM-DC), and PGE2-induced IL-10 is a key regulator of the BM-DC pro-inflammatory phenotype. BM-DC may be considered as an important model to study complex interactions between endogenous mediators, and autocrine IL-10 plays a pivotal role in the crossregulation of AA-derived lipid mediators, cytokines, and NO, with critical effects on immune and inflammatory responses.

The protective effect of astaxanthin on fetal alcohol spectrum disorder in mice.

PubMed

Zheng, Dong; Li, Yi; He, Lei; Tang, Yamei; Li, Xiangpen; Shen, Qingyu; Yin, Deling; Peng, Ying

2014-09-01

Astaxanthin is a strong antioxidant with the ability of reducing the markers of inflammation. To explore the protective effect of astaxanthin on maternal ethanol induced embryonic deficiency, and to investigate the underlying mechanisms, we detected the morphology, expression of neural marker genes, oxidative stress indexes, and inflammatory factors in mice model of fetal alcohol spectrum disorder with or without astaxanthin pretreatment. Our results showed that astaxanthin blocked maternal ethanol induced retardation of embryonic growth, and the down-regulation of neural marker genes, Otx1 and Sox2. Moreover, astaxanthin also reversed the increases of malondialdehyde (MDA), hydrogen peroxide (H2O2), and the decrease of glutathione peroxidase (GPx) in fetal alcohol spectrum disorder. In addition, maternal ethanol induced up-regulation of toll-like receptor 4 (TLR4), and the down-streaming myeloid differentiation factor 88 (MyD88), NF-κB, TNF-α, and IL-1β in embryos, and this was inhibited by astaxanthin pretreatment. These results demonstrated a protective effect of astaxanthin on fetal alcohol spectrum disorder, and suggested that oxidative stress and TLR4 signaling associated inflammatory reaction are involved in this process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis

PubMed Central

Erlich, Ziv; Hourizadeh, Aria; Ofir-Birin, Yifat; Croker, Ben A.; Regev-Rudzki, Neta; Edry-Botzer, Liat

2017-01-01

Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the “find me” and “eat me” signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such “eat me” signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific “find me” and “eat me” signals. PMID:28650960

Microglia During Development and Aging

PubMed Central

Harry, G. Jean

2013-01-01

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, andaxonal degeneration. Changes inmicroglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microgliapotentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. PMID:23644076