Adenosine and inflammation: what's new on the horizon?

PubMed

Antonioli, Luca; Csóka, Balázs; Fornai, Matteo; Colucci, Rocchina; Kókai, Endre; Blandizzi, Corrado; Haskó, György

2014-08-01

Adenosine contributes to the maintenance of tissue integrity by modulating the immune system. Encouraging results have emerged with adenosine receptor ligands for the management of several inflammatory conditions in preclinical and clinical settings. However, therapeutic applications of these drugs are sometimes complicated by the occurrence of serious adverse effects. The scientific community is making intensive efforts to design novel adenosine receptor ligands endowed with greater selectivity or to develop innovative compounds acting as allosteric receptor modulators. In parallel, research is focusing on novel pharmacological entities (designated as adenosine-regulating agents) that can increase, in a site- and event-specific manner, adenosine concentrations at the inflammatory site, thereby minimizing the adverse systemic effects of adenosine. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Nervous System and Gastrointestinal Function

ERIC Educational Resources Information Center

Altaf, Muhammad A.; Sood, Manu R.

2008-01-01

The enteric nervous system is an integrative brain with collection of neurons in the gastrointestinal tract which is capable of functioning independently of the central nervous system (CNS). The enteric nervous system modulates motility, secretions, microcirculation, immune and inflammatory responses of the gastrointestinal tract. Dysphagia,…

'Drugs from bugs': bacterial effector proteins as promising biological (immune-) therapeutics.

PubMed

Rüter, Christian; Hardwidge, Philip R

2014-02-01

Immune system malfunctions cause many of the most severe human diseases. The immune system has evolved primarily to control bacterial, viral, fungal, and parasitic infections. In turn, over millions of years of coevolution, microbial pathogens have evolved various mechanisms to control and modulate the host immune system for their own benefit and survival. For example, many bacterial pathogens use virulence proteins to modulate and exploit target cell mechanisms. Our understanding of these bacterial strategies opens novel possibilities to exploit 'microbial knowledge' to control excessive immune reactions. Gaining access to strategies of microbial pathogens could lead to potentially huge benefits for the therapy of inflammatory diseases. Most work on bacterial pathogen effector proteins has the long-term aim of neutralizing the infectious capabilities of the pathogen. However, attenuated pathogens and microbial products have been used for over a century with overwhelming success in the form of vaccines to induce specific immune responses that protect against the respective infectious diseases. In this review, we focus on bacterial effector and virulence proteins capable of modulating and suppressing distinct signaling pathways with potentially desirable immune-modulating effects for treating unrelated inflammatory diseases. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Herbal medicine IMOD suppresses LPS-induced production of proinflammatory cytokines in human dendritic cells

PubMed Central

Mirzaee, Saeedeh; Drewniak, Agata; Sarrami-Forooshani, Ramin; Kaptein, Tanja M.; Gharibdoost, Farhad; Geijtenbeek, Teunis B. H.

2015-01-01

Traditional medicines that stimulate or modulate the immune system can be used as innovative approaches to treat immunological diseases. The herbal medicine IMOD has been shown to strongly modulate immune responses in several animal studies as well as in clinical trials. However, little is known about the mechanisms of IMOD to modulate immunity. Here we have investigated whether IMOD modulates the immunological function of human dendritic cells (DCs). IMOD alone did not induce DC maturation nor production of cytokines. Notably, IMOD decreased the production of pro-inflammatory cytokines IL-6, IL-12 p70, and TNFα by LPS-activated DCs at both mRNA and protein levels in a dose dependent manner. In contrast, treatment with IMOD did not affect LPS induced-production of the anti-inflammatory cytokine IL-10. Furthermore, IMOD inhibited T cell activation/proliferation by LPS-treated DCs and skewed T-cells responses toward the T helper type 2 polarization. These data strongly indicate that IMOD has a potent immunomodulatory ability that affects TLR signaling and thereby modulates DC function. Insight into the immunomodulatory effect of herbal medicine IMOD may provide innovative strategies to affect the immune system and to help combat various diseases. PMID:25870561

sHLA-I Contamination, a novel mechanism to explain ex vivo/in vitro modulation of IL-10 synthesis and release in CD8(+) T lymphocytes and in neutrophils following intravenous immunoglobulin infusion.

PubMed

Ghio, Massimo; Contini, Paola; Setti, Maurizio; Ubezio, Gianluca; Mazzei, Clemente; Tripodi, Gino

2010-05-01

Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders; among others, they could decrease pro-inflammatory cytokine levels and also induce anti-inflammatory cytokines. Ex vivo analysis of cells from ten IVIG recipients showed significant increase of IL-10 mRNA and intra-cellular IL-10 molecules in both leukotypes. In vitro comparable results were obtained incubating CD8(+) T lymphocytes and neutrophils from healthy donors with IVIG. sHLA-I and/or sFasL immunodepletion abolished IL-10 modulation. Co-culture with contaminant-free IgM or MabThera did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced IL-10-mRNA in both leukotypes to levels comparable to those obtained with IVIG incubation. As IVIG infusion involves administration of soluble contaminants, these data consent to speculate that IVIG might modulate IL-10 via the immunomodulatory activities of sHLA-I contaminant molecules inducing transcriptional and post-transcriptional modulation of IL-10 in CD8(+) T lymphocytes and neutrophils.

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.

Gut Microbiota-Immune System Crosstalk and Pancreatic Disorders

PubMed Central

Saviano, A.; Newton, E. E.; Serricchio, M. L.; Dal Lago, A. A.

2018-01-01

Gut microbiota is key to the development and modulation of the mucosal immune system. It plays a central role in several physiological functions, in the modulation of inflammatory signaling and in the protection against infections. In healthy states, there is a perfect balance between commensal and pathogens, and microbiota and the immune system interact to maintain gut homeostasis. The alteration of such balance, called dysbiosis, determines an intestinal bacterial overgrowth which leads to the disruption of the intestinal barrier with systemic translocation of pathogens. The pancreas does not possess its own microbiota, and it is believed that inflammatory and neoplastic processes affecting the gland may be linked to intestinal dysbiosis. Increasing research evidence testifies a correlation between intestinal dysbiosis and various pancreatic disorders, but it remains unclear whether dysbiosis is the cause or an effect. The analysis of specific alterations in the microbiome profile may permit to develop novel tools for the early detection of several pancreatic disorders, utilizing samples, such as blood, saliva, and stools. Future studies will have to elucidate the mechanisms by which gut microbiota is modulated and how it tunes the immune system, in order to be able to develop innovative treatment strategies for pancreatic disorders. PMID:29563853

Acetylcholine and the alpha 7 nicotinic receptor: a potential therapeutic target for the treatment of periodontal disease?

PubMed Central

2013-01-01

Objectives The aim of this review is to examine the evidence for a functional cholinergic system operating within the periodontium and determine the evidence for its role in periodontal immunity. Introduction Acetylcholine can influence the immune system via the ‘cholinergic anti-inflammatory pathway’. This pathway is mediated by the vagus nerve which releases acetylcholine to interact with the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) on proximate immuno-regulatory cells. Activation of the α7nAChR on these cells leads to down-regulated expression of pro-inflammatory mediators and thus regulates localised inflammatory responses. The role of the vagus nerve in periodontal pathophysiology is currently unknown. However, non-neuronal cells can also release acetylcholine and express the α7nAChR; these include keratinocytes, fibroblasts, T cells, B cells and macrophages. Therefore, by both autocrine and paracrine methods non-neuronal acetylcholine can also be hypothesised to modulate the localised immune response. Methods A Pubmed database search was performed for studies providing evidence for a functional cholinergic system operating in the periodontium. In addition, literature on the role of the ‘cholinergic anti-inflammatory pathway’ in modulating the immune response was extrapolated to hypothesise that similar mechanisms of immune regulation occur within the periodontium. Conclusion The evidence suggests a functional nonneuronal ‘cholinergic anti-inflammatory pathway’ may operate in the periodontium and that this may be targeted therapeutically to treat periodontal disease. PMID:22777144

Inflammatory Responses in Brain Ischemia

PubMed Central

Kawabori, Masahito; Yenari, Midori A.

2017-01-01

Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke. PMID:25666795

Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases

PubMed Central

Lin, Gu-Jiun; Huang, Shing-Hwa; Chen, Shyi-Jou; Wang, Chih-Hung; Chang, Deh-Ming; Sytwu, Huey-Kang

2013-01-01

Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease. PMID:23727938

Immuno-modulation and anti-inflammatory benefits of antibiotics: the example of tilmicosin.

PubMed

Buret, André G

2010-01-01

Exaggerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects.

Immuno-modulation and anti-inflammatory benefits of antibiotics: The example of tilmicosin

PubMed Central

Buret, André G.

2010-01-01

Exagerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects. PMID:20357951

Neural circuitry and immunity

PubMed Central

Pavlov, Valentin A.; Tracey, Kevin J.

2015-01-01

Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuroimmune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases defines the emerging field of Bioelectronic Medicine. PMID:26512000

Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases

PubMed Central

Boyapati, Ray K.; Tamborska, Arina; Dorward, David A.; Ho, Gwo-Tzer

2017-01-01

Mitochondrial DNA (mtDNA) has many similarities with bacterial DNA because of their shared common ancestry. Increasing evidence demonstrates mtDNA to be a potent danger signal that is recognised by the innate immune system and can directly modulate the inflammatory response. In humans, elevated circulating mtDNA is found in conditions with significant tissue injury such as trauma and sepsis and increasingly in chronic organ-specific and systemic illnesses such as steatohepatitis and systemic lupus erythematosus. In this review, we examine our current understanding of mtDNA-mediated inflammation and how the mechanisms regulating mitochondrial homeostasis and mtDNA release represent exciting and previously under-recognised important factors in many human inflammatory diseases, offering many new translational opportunities. PMID:28299196

Chrysin suppresses mast cell-mediated allergic inflammation: Involvement of calcium, caspase-1 and nuclear factor-{kappa}B

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

Bae, Yunju; Lee, Soyoung; Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr

A great number of people are suffering from allergic inflammatory diseases such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid contained in propolis, blue passion flower, and fruits. Several studies reported that chrysin has beneficial effects including anti-tumor and anti-oxidant activities. The aim of the present study was to elucidate whether chrysin modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. Chrysin inhibited immediate-type systemic hypersensitivitymore » and serum histamine release. Chrysin attenuated immunoglobulin E-mediated local anaphylaxis. These inhibitory effects of chrysin on the systemic and local allergic reaction were more potent than cromolyn, a known anti-allergic drug. Chrysin reduced histamine release from mast cells. The inhibitory effect of chrysin on the histamine release was mediated by the modulation of intracellular calcium. In addition, chrysin decreased gene expression of pro-inflammatory cytokines such as, tumor necrosis factor-{alpha}, IL (interleukin)-1{beta}, IL-4, and IL-6 in mast cells. The inhibitory effect of chrysin on the pro-inflammatory cytokine was nuclear factor-{kappa}B and caspase-1 dependent. Our findings provide evidence that chrysin inhibits mast cell-derived allergic inflammatory reactions by blocking histamine release and pro-inflammatory cytokine expression, and suggest the mechanisms of action. Furthermore, in vivo and in vitro anti-allergic inflammatory effect of chrysin suggests a possible therapeutic application of this agent in allergic inflammatory diseases. - Research Highlights: > Discovery of drugs for the allergic inflammation is important in human health. > Chrysin is a natural flavonoid contained in propolis, blue passion flower, and fruits. > Chrysin inhibited systemic and local hypersensitivity, and serum histamine release. > Chrysin decreased inflammatory cytokines through the inhibition of NF-{kappa}B and caspase-1. > Chrysin might be a candidate for the treatment of allergic inflammatory diseases.« less

Schistosoma mansoni Tegument (Smteg) Induces IL-10 and Modulates Experimental Airway Inflammation.

PubMed

Marinho, Fábio Vitarelli; Alves, Clarice Carvalho; de Souza, Sara C; da Silva, Cintia M G; Cassali, Geovanni D; Oliveira, Sergio C; Pacifico, Lucila G G; Fonseca, Cristina T

2016-01-01

Previous studies have demonstrated that S. mansoni infection and inoculation of the parasite eggs and antigens are able to modulate airways inflammation induced by OVA in mice. This modulation was associated to an enhanced production of interleukin-10 and to an increased number of regulatory T cells. The S. mansoni schistosomulum is the first stage to come into contact with the host immune system and its tegument represents the host-parasite interface. The schistosomula tegument (Smteg) has never been studied in the context of modulation of inflammatory disorders, although immune evasion mechanisms take place in this phase of infection to guarantee the persistence of the parasite in the host. The aim of this study was to evaluate the Smteg ability to modulate inflammation in an experimental airway inflammation model induced by OVA and to characterize the immune factors involved in this modulation. To achieve the objective, BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with OVA aerosol after Smteg intraperitoneal inoculation. Protein extravasation and inflammatory cells were assessed in bronchoalveolar lavage and IgE levels were measured in serum. Additionally, lungs were excised for histopathological analyses, cytokine measurement and characterization of the cell populations. Inoculation with Smteg led to a reduction in the protein levels in bronchoalveolar lavage (BAL) and eosinophils in both BAL and lung tissue. In the lung tissue there was a reduction in inflammatory cells and collagen deposition as well as in IL-5, IL-13, IL-25 and CCL11 levels. Additionally, a decrease in specific anti-OVA IgE levels was observed. The reduction observed in these inflammatory parameters was associated with increased levels of IL-10 in lung tissues. Furthermore, Smteg/asthma mice showed high percentage of CD11b+F4/80+IL-10+ and CD11c+CD11b+IL-10+ cells in lungs. Taken together, these findings demonstrate that S. mansoni schistosomula tegument can modulates experimental airway inflammation.

Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases.

PubMed

Ciechomska, Marzena; O'Reilly, Steven

2016-01-01

Systemic inflammatory rheumatic diseases are considered as autoimmune diseases, meaning that the balance between recognition of pathogens and avoidance of self-attack is impaired and the immune system attacks and destroys its own healthy tissue. Treatment with conventional Disease Modifying Antirheumatic Drugs (DMARDs) and/or Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) is often associated with various adverse reactions due to unspecific and toxic properties of those drugs. Although biologic drugs have largely improved the outcome in many patients, such drugs still pose significant problems and fail to provide a solution to all patients. Therefore, development of more effective treatments and improvements in early diagnosis of rheumatic diseases are badly needed in order to increase patient's functioning and quality of life. The reversible nature of epigenetic mechanisms offers a new class of drugs that modulate the immune system and inflammation. In fact, epigenetic drugs are already in use in some types of cancer or cardiovascular diseases. Therefore, epigenetic-based therapeutics that control autoimmunity and chronic inflammatory process have broad implications for the pathogenesis, diagnosis, and management of rheumatic diseases. This review summarises the latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities and inflammation of rheumatic diseases.

Nutraceuticals in rodent models as potential treatments for human Inflammatory Bowel Disease.

PubMed

Ghattamaneni, Naga K R; Panchal, Sunil K; Brown, Lindsay

2018-04-20

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation of all or part of the digestive tract. Nutraceuticals include bioactive compounds such as polyphenols with anti-inflammatory activities, thus these products have the potential to treat chronic inflammatory diseases. We have emphasized the role of nutraceuticals in ameliorating the symptoms of IBD in rodent models of human IBD through modulation of key pathogenic mechanisms including dysbiosis, oxidative stress, increased inflammatory cytokines, immune system dysregulation, and inflammatory cell signaling pathways. Nutraceuticals have an important role in IBD patients as a preventive approach to extend remission phases and as a therapeutic intervention to suppress active IBD. Further clinical trials on nutraceuticals with positive results in rodent models are warranted. Copyright © 2018. Published by Elsevier Ltd.

Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

PubMed

Bassi, Gabriel S; do C Malvar, David; Cunha, Thiago M; Cunha, Fernando Q; Kanashiro, Alexandre

2016-08-01

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

HDAC inhibitors: modulating leukocyte differentiation, survival, proliferation and inflammation.

PubMed

Sweet, Matthew J; Shakespear, Melanie R; Kamal, Nabilah A; Fairlie, David P

2012-01-01

Therapeutic effects of histone deacetylase (HDAC) inhibitors in cancer models were first linked to their ability to cause growth arrest and apoptosis of tumor cells. It is now clear that these agents also have pleiotropic effects on angiogenesis and the immune system, and some of these properties are likely to contribute to their anti-cancer activities. It is also emerging that inhibitors of specific HDACs affect the differentiation, survival and/or proliferation of distinct immune cell populations. This is true for innate immune cells such as macrophages, as well as cells of the acquired immune system, for example, T-regulatory cells. These effects may contribute to therapeutic profiles in some autoimmune and chronic inflammatory disease models. Here, we review our current understanding of how classical HDACs (HDACs 1-11) and their inhibitors impact on differentiation, survival and proliferation of distinct leukocyte populations, as well as the likely relevance of these effects to autoimmune and inflammatory disease processes. The ability of HDAC inhibitors to modulate leukocyte survival may have implications for the rationale of developing selective inhibitors as anti-inflammatory drugs.

Intestinal barrier: A gentlemen’s agreement between microbiota and immunity

PubMed Central

Caricilli, Andrea Moro; Castoldi, Angela; Câmara, Niels Olsen Saraiva

2014-01-01

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host’s adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier. PMID:24891972

Functional evidence for the inflammatory reflex in teleosts: A novel α7 nicotinic acetylcholine receptor modulates the macrophage response to dsRNA.

PubMed

Torrealba, Débora; Balasch, Joan Carles; Criado, Manuel; Tort, Lluís; Mackenzie, Simon; Roher, Nerea

2018-07-01

The inflammatory reflex modulates the innate immune system, keeping in check the detrimental consequences of overstimulation. A key player controlling the inflammatory reflex is the alpha 7 acetylcholine receptor (α7nAChR). This receptor is one of the signalling molecules regulating cytokine expression in macrophages. In this study, we characterize a novel teleost α7nAChR. Protein sequence analysis shows a high degree of conservation with mammalian orthologs and trout α7nAChR has all the features and essential amino acids to form a fully functional receptor. We demonstrate that trout macrophages can bind α-bungarotoxin (α-BTX), a competitive antagonist for α7nAChRs. Moreover, nicotine stimulation produces a decrease in pro-inflammatory cytokine expression after stimulation with poly(I:C). These results suggest the presence of a functional α7nAChR in the macrophage plasma membrane. Further, in vivo injection of poly(I:C) induced an increase in serum ACh levels in rainbow trout. Our results manifest for the first time the functional conservation of the inflammatory reflex in teleosts. Copyright © 2018 Elsevier Ltd. All rights reserved.

Diet and Inflammation: Possible Effects on Immunity, Chronic Diseases, and Life Span.

PubMed

Ricordi, Camillo; Garcia-Contreras, Marta; Farnetti, Sara

2015-01-01

Chronic inflammation negatively impacts all physiological functions, causing an array of degenerative conditions including diabetes; cancer; cardiovascular, osteo-articular, and neurodegenerative diseases; autoimmunity disorders; and aging. In particular, there is a growing knowledge of the role that gene transcription factors play in the inflammatory process. Obesity, metabolic syndrome, and diabetes represent multifactorial conditions resulting from improper balances of hormones and gene expression. In addition, these conditions have a strong inflammatory component that can potentially be impacted by the diet. It can reduce pro-inflammatory eicosanoids that can alter hormonal signaling cascades to the modulation of the innate immune system and gene transcription factors. Working knowledge of the impact of how nutrients, especially dietary fatty acids and polyphenols, can impact these various molecular targets makes it possible to develop a general outline of an anti-inflammatory diet that offers a unique, nonpharmacological approach in treating obesity, metabolic syndrome, and diabetes. Several important bioactive dietary components can exert their effect through selected inflammatory pathways that can affect metabolic and genetic changes. In fact, dietary components that can modulate glucose and insulin levels, as well as any other mediator that can activate nuclear factor-kB, can also trigger inflammation through common pathway master switches.

Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement

PubMed Central

Goodman, S. B.; Gibon, E.; Pajarinen, J.; Lin, T.-H.; Keeney, M.; Ren, P.-G.; Nich, C.; Yao, Z.; Egashira, K.; Yang, F.; Konttinen, Y. T.

2014-01-01

Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants. PMID:24478281

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

GanedenBC30 cell wall and metabolites: anti-inflammatory and immune modulating effects in vitro.

PubMed

Jensen, Gitte S; Benson, Kathleen F; Carter, Steve G; Endres, John R

2010-03-24

This study was performed to evaluate anti-inflammatory and immune modulating properties of the probiotic, spore-forming bacterial strain: Bacillus coagulans: GBI-30, (PTA-6086, GanedenBC30TM). In addition, cell wall and metabolite fractions were assayed separately to address whether biological effects were due to cell wall components only, or whether secreted compounds from live bacteria had additional biological properties. The spores were heat-activated, and bacterial cultures were grown. The culture supernatant was harvested as a source of metabolites (MTB), and the bacteria were used to isolate cell wall fragments (CW). Both of these fractions were compared in a series of in vitro assays. Both MTB and CW inhibited spontaneous and oxidative stress-induced ROS formation in human PMN cells and increased the phagocytic activity of PMN cells in response to bacteria-like carboxylated fluorospheres. Both fractions supported random PMN and f-MLP-directed PMN cell migration, indicating a support of immune surveillance and antibacterial defense mechanisms. In contrast, low doses of both fractions inhibited PMN cell migration towards the inflammatory mediators IL-8 and LTB4. The anti-inflammatory activity was strongest for CW, where the PMN migration towards IL-8 was inhibited down to dilutions of 1010.Both MTB and CW induced the expression of the CD69 activation marker on human CD3- CD56+ NK cells, and enhanced the expression of CD107a when exposed to K562 tumor cells in vitro.The fractions directly modulated cytokine production, inducing production of the Th2 cytokines IL-4, IL-6, and IL-10, and inhibiting production of IL-2.Both fractions further modulated mitogen-induced cytokine production in the following manner: Both fractions enhanced the PHA-induced production of IL-6 and reduced the PHA-induced production of TNF-alpha. Both fractions enhanced the PWM-induced production of TNF-alpha and IFN-gamma. In addition, MTB also enhanced both the PHA- and the PWM-induced expression of IL-10. The data suggest that consumption of GanedenBC30TM may introduce both cell wall components and metabolites that modulate inflammatory processes in the gut. Both the cell wall and the supernatant possess strong immune modulating properties in vitro. The anti-inflammatory effects, combined with direct induction of IL-10, are of interest with respect to possible treatment of inflammatory bowel diseases as well as in support of a healthy immune system.

GanedenBC30™ cell wall and metabolites: anti-inflammatory and immune modulating effects in vitro

PubMed Central

2010-01-01

Background This study was performed to evaluate anti-inflammatory and immune modulating properties of the probiotic, spore-forming bacterial strain: Bacillus coagulans: GBI-30, (PTA-6086, GanedenBC30TM). In addition, cell wall and metabolite fractions were assayed separately to address whether biological effects were due to cell wall components only, or whether secreted compounds from live bacteria had additional biological properties. The spores were heat-activated, and bacterial cultures were grown. The culture supernatant was harvested as a source of metabolites (MTB), and the bacteria were used to isolate cell wall fragments (CW). Both of these fractions were compared in a series of in vitro assays. Results Both MTB and CW inhibited spontaneous and oxidative stress-induced ROS formation in human PMN cells and increased the phagocytic activity of PMN cells in response to bacteria-like carboxylated fluorospheres. Both fractions supported random PMN and f-MLP-directed PMN cell migration, indicating a support of immune surveillance and antibacterial defense mechanisms. In contrast, low doses of both fractions inhibited PMN cell migration towards the inflammatory mediators IL-8 and LTB4. The anti-inflammatory activity was strongest for CW, where the PMN migration towards IL-8 was inhibited down to dilutions of 1010. Both MTB and CW induced the expression of the CD69 activation marker on human CD3- CD56+ NK cells, and enhanced the expression of CD107a when exposed to K562 tumor cells in vitro. The fractions directly modulated cytokine production, inducing production of the Th2 cytokines IL-4, IL-6, and IL-10, and inhibiting production of IL-2. Both fractions further modulated mitogen-induced cytokine production in the following manner: Both fractions enhanced the PHA-induced production of IL-6 and reduced the PHA-induced production of TNF-alpha. Both fractions enhanced the PWM-induced production of TNF-alpha and IFN-gamma. In addition, MTB also enhanced both the PHA- and the PWM-induced expression of IL-10. Conclusion The data suggest that consumption of GanedenBC30TM may introduce both cell wall components and metabolites that modulate inflammatory processes in the gut. Both the cell wall and the supernatant possess strong immune modulating properties in vitro. The anti-inflammatory effects, combined with direct induction of IL-10, are of interest with respect to possible treatment of inflammatory bowel diseases as well as in support of a healthy immune system. PMID:20331905

Dysfunctional brain-bone marrow communication: a paradigm shift in the pathophysiology of hypertension.

PubMed

Santisteban, Monica M; Zubcevic, Jasenka; Baekey, David M; Raizada, Mohan K

2013-08-01

It is widely accepted that the pathophysiology of hypertension involves autonomic nervous system dysfunction, as well as a multitude of immune responses. However, the close interplay of these systems in the development and establishment of high blood pressure and its associated pathophysiology remains elusive and is the subject of extensive investigation. It has been proposed that an imbalance of the neuro-immune systems is a result of an enhancement of the "proinflammatory sympathetic" arm in conjunction with dampening of the "anti-inflammatory parasympathetic" arm of the autonomic nervous system. In addition to the neuronal modulation of the immune system, it is proposed that key inflammatory responses are relayed back to the central nervous system and alter the neuronal communication to the periphery. The overall objective of this review is to critically discuss recent advances in the understanding of autonomic immune modulation, and propose a unifying hypothesis underlying the mechanisms leading to the development and maintenance of hypertension, with particular emphasis on the bone marrow, as it is a crucial meeting point for neural, immune, and vascular networks.

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.

PubMed

Racke, M K; Bonomo, A; Scott, D E; Cannella, B; Levine, A; Raine, C S; Shevach, E M; Röcken, M

1994-11-01

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.

Cyanidin-3-O-Glucoside Modulates the In Vitro Inflammatory Crosstalk between Intestinal Epithelial and Endothelial Cells.

PubMed

Ferrari, Daniela; Cimino, Francesco; Fratantonio, Deborah; Molonia, Maria Sofia; Bashllari, Romina; Busà, Rossana; Saija, Antonella; Speciale, Antonio

2017-01-01

Intestinal epithelium represents a protective physical barrier and actively contributes to the mucosal immune system. Polarized basolateral intestinal secretion of inflammatory mediators, followed by activation of NF- κ B signaling and inflammatory pathways in endothelial cells, efficiently triggers extravasation of neutrophils from the vasculature, therefore contributing to the development and maintenance of intestinal inflammation. Proper regulation of NF- κ B activation at the epithelial interface is crucial for the maintenance of physiological tissue homeostasis. Many papers reported that anthocyanins, a group of compounds belonging to flavonoids, possess anti-inflammatory effects and modulate NF- κ B activity. In this study, by using a coculture in vitro system, we aimed to evaluate the effects of TNF- α -stimulated intestinal cells on endothelial cells activation, as well as the protective effects of cyanidin-3-glucoside (C3G). In this model, TNF- α induced nuclear translocation of NF- κ B and TNF- α and IL-8 gene expression in Caco-2 cells, whereas C3G pretreatment dose-dependently reduced these effects. Furthermore, TNF- α -stimulated Caco-2 cells induced endothelial cells activation with increased E-selectin and VCAM-1 mRNA, leukocyte adhesion, and NF- κ B levels in HUVECs, which were inhibited by C3G. We demonstrated that selective inhibition of the NF- κ B pathway in epithelial cells represents the main mechanism by which C3G exerts these protective effects. Thus, anthocyanins could contribute to the management of chronic gut inflammatory diseases.

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.

Topical Modulation of the Burn Wound Inflammatory Response to Improve Short and Long Term Outcomes

DTIC Science & Technology

2017-10-01

casualty, treatment, organ failure, systemic inflammatory response syndrome , thermal injury, wound model, intervention 3. ACCOMPLISHMENTS:   What...thickness burns have a blister response. Using human eye or H&E studies, we did not observe any blisters in the pig model. However, the OCT...the deeper the partial thickness burn, the bigger the blister, until it gets close to full-thickness burns. The full-thickness burns are dry and

Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA.

PubMed

Webb, Lindsay M; Guerau-de-Arellano, Mireia

2017-06-01

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The inflammatory and neurodegenerative pathways driving MS are modulated by DNA, lysine, and arginine methylation, as evidenced by studies made possible by novel tools for methylation detection or loss of function. We present evidence that MS is associated with genetic variants and metabolic changes that impact on methylation. Further, we comprehensively review current understanding of how methylation can impact on central nervous system (CNS) resilience and neuroregenerative potential, as well as inflammatory versus regulatory T helper (Th) cell balance. These findings are discussed in the context of therapeutic relevance for MS, with broad implications in other neurologic and immune-mediated diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

PubMed Central

Neumann, Silke; Shields, Nicholas J.; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N.

2015-01-01

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells. PMID:26690125

Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective.

PubMed

Neumann, Silke; Shields, Nicholas J; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N

2015-12-04

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

Sigma-1 receptor and inflammatory pain.

PubMed

Gris, Georgia; Cobos, Enrique José; Zamanillo, Daniel; Portillo-Salido, Enrique

2015-06-01

The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain. Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary. Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.

N-3 Polyunsaturated Fatty Acids and Inflammation in Obesity: Local Effect and Systemic Benefit

PubMed Central

Huang, Feiruo

2015-01-01

Overwhelming consensus emerges among countless evidences that obesity is characterized by a chronic low-grade inflammation in the adipose tissue (AT), which subsequently develops into a systemic inflammatory state contributing to obesity-associated diseases. N-3 Polyunsaturated fatty acids (n-3 PUFA), known as important modulators participating in inflammatory process, turn out to be an effective mitigating strategy dealing with local and systemic inflammation observed in obesity. Some of the effects of n-3 PUFA are brought about by regulation of gene expression through interacting with nuclear receptors and transcription factors; other effects are elicited by modulation of the amount and type of mediator derived from PUFAs. The metabolic effects of n-3 PUFA mainly result from their interactions with several organ systems, not limited to AT. Notably, the attenuation of inflammation in hard-hit AT, in turn, contributes to reducing circulating concentrations of proinflammatory cytokines and detrimental metabolic derivatives, which is beneficial for the function of other involved organs. The present review highlights a bridging mechanism between n-3 PUFA-mediated inflammation relief in AT and systemic benefits. PMID:26339623

N-3 Polyunsaturated Fatty Acids and Inflammation in Obesity: Local Effect and Systemic Benefit.

PubMed

Wang, Yue; Huang, Feiruo

2015-01-01

Overwhelming consensus emerges among countless evidences that obesity is characterized by a chronic low-grade inflammation in the adipose tissue (AT), which subsequently develops into a systemic inflammatory state contributing to obesity-associated diseases. N-3 Polyunsaturated fatty acids (n-3 PUFA), known as important modulators participating in inflammatory process, turn out to be an effective mitigating strategy dealing with local and systemic inflammation observed in obesity. Some of the effects of n-3 PUFA are brought about by regulation of gene expression through interacting with nuclear receptors and transcription factors; other effects are elicited by modulation of the amount and type of mediator derived from PUFAs. The metabolic effects of n-3 PUFA mainly result from their interactions with several organ systems, not limited to AT. Notably, the attenuation of inflammation in hard-hit AT, in turn, contributes to reducing circulating concentrations of proinflammatory cytokines and detrimental metabolic derivatives, which is beneficial for the function of other involved organs. The present review highlights a bridging mechanism between n-3 PUFA-mediated inflammation relief in AT and systemic benefits.

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.

Immunological Effects of Probiotics and their Significance to Human Health

NASA Astrophysics Data System (ADS)

Gill, Harsharn S.; Grover, Sunita; Batish, Virender K.; Gill, Preet

Probiotics are defined as live microorganisms which when administered in adequate amounts confer a health benefit upon the host (FAO/WHO, 2001). Lactic acid bacteria, particularly Lactobacillus and Bifidobacterium species are commonly used as probiotics. Other less commonly used probiotics include the yeast Sacchromyces cerevisiae and some non-pathogenic Escherichia coli and Bacillus species. Studies over the past 20 years have demonstrated that probiotic intake is able to confer a range of health benefits including modulation of the immune system, protection against gastrointestinal and respiratory tract infections, lowering of blood cholesterol levels, attenuation of overt immuno-inflammatory disorders (such as inflammatory bowel disease, allergies) and anti-cancer effects. However, the strongest clinical evidence for probiotics relates to their effectiveness in improving gut health and modulating (via stimulation or regulation) the host immune system. This chapter provides an overview of the current status of our knowledge regarding the immunostimulatory and immunoregulatory effects of probiotics on the immune system and their significance to human health.

Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia

PubMed Central

Amici, Stephanie A.; Dong, Joycelyn; Guerau-de-Arellano, Mireia

2017-01-01

Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the complexity of macrophage function can only be achieved by the existence of varied, plastic and tridimensional macrophage phenotypes. Understanding how tissue macrophages integrate environmental signals via molecular programs to define pathogen/injury inflammatory responses provides an opportunity to better understand the multilayered nature of macrophages, as well as target and modulate cellular programs to control excessive inflammation. This is particularly important in MS and other neuroinflammatory diseases, where chronic inflammatory macrophage and microglial responses may contribute to pathology. Here, we perform a comprehensive review of our current understanding of how molecular pathways modulate tissue macrophage phenotype, covering both classic pathways and the emerging role of microRNAs, receptor-tyrosine kinases and metabolism in macrophage phenotype. In addition, we discuss pathway parallels in microglia, novel markers helpful in the identification of peripheral macrophages versus microglia and markers linked to their phenotype. PMID:29176977

The Role of Heparan Sulfate in Inflammation, and the Development of Biomimetics as Anti-Inflammatory Strategies.

PubMed

Farrugia, Brooke L; Lord, Megan S; Melrose, James; Whitelock, John M

2018-04-01

Key events that occur during inflammation include the recruitment, adhesion, and transmigration of leukocytes from the circulation to the site of inflammation. These events are modulated by chemokines, integrins, and selectins and the interaction of these molecules with glycosaminoglycans, predominantly heparan sulfate (HS). The development of HS/heparin mimetics that interfere or inhibit the interactions that occur between glycosaminoglycans and modulators of inflammation holds great potential for use as anti-inflammatory therapeutics. This review will detail the role of HS in the events that occur during inflammation, their interaction and modulation of inflammatory mediators, and the current advances in the development of HS/heparin mimetics as anti-inflammatory biotherapeutics.

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.

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

Modulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver by probiotics

PubMed Central

Plaza-Diaz, Julio; Gomez-Llorente, Carolina; Fontana, Luis; Gil, Angel

2014-01-01

The potential for the positive manipulation of the gut microbiome through the introduction of beneficial microbes, as also known as probiotics, is currently an active area of investigation. The FAO/WHO define probiotics as live microorganisms that confer a health benefit to the host when administered in adequate amounts. However, dead bacteria and bacterial molecular components may also exhibit probiotic properties. The results of clinical studies have demonstrated the clinical potential of probiotics in many pathologies, such as allergic diseases, diarrhea, inflammatory bowel disease and viral infection. Several mechanisms have been proposed to explain the beneficial effects of probiotics, most of which involve gene expression regulation in specific tissues, particularly the intestine and liver. Therefore, the modulation of gene expression mediated by probiotics is an important issue that warrants further investigation. In the present paper, we performed a systematic review of the probiotic-mediated modulation of gene expression that is associated with the immune system and inflammation. Between January 1990 to February 2014, PubMed was searched for articles that were published in English using the MeSH terms “probiotics" and "gene expression" combined with “intestines", "liver", "enterocytes", "antigen-presenting cells", "dendritic cells", "immune system", and "inflammation". Two hundred and five original articles matching these criteria were initially selected, although only those articles that included specific gene expression results (77) were later considered for this review and separated into three major topics: the regulation of immunity and inflammatory gene expression in the gut, in inflammatory diseases of the gut and in the liver. Particular strains of Bifidobacteria, Lactobacilli, Escherichia coli, Propionibacterium, Bacillus and Saccharomyces influence the gene expression of mucins, Toll-like receptors, caspases, nuclear factor-κB, and interleukins and lead mainly to an anti-inflammatory response in cultured enterocytes. In addition, the interaction of commensal bacteria and probiotics with the surface of antigen-presenting cells in vitro results in the downregulation of pro-inflammatory genes that are linked to inflammatory signaling pathways, whereas other anti-inflammatory genes are upregulated. The effects of probiotics have been extensively investigated in animal models ranging from fish to mice, rats and piglets. These bacteria induce a tolerogenic and hyporesponsive immune response in which many genes that are related to the immune system, in particular those genes expressing anti-inflammatory cytokines, are upregulated. By contrast, information related to gene expression in human intestinal cells mediated by the action of probiotics is scarce. There is a need for further clinical studies that evaluate the mechanism of action of probiotics both in healthy humans and in patients with chronic diseases. These types of clinical studies are necessary for addressing the influence of these microorganisms in gene expression for different pathways, particularly those that are associated with the immune response, and to better understand the role that probiotics might have in the prevention and treatment of disease. PMID:25400447

Role of training and detraining on inflammatory and metabolic profile in infarcted rats: influences of cardiovascular autonomic nervous system.

PubMed

Rodrigues, Bruno; Santana, Aline Alves; Santamarina, Aline Boveto; Oyama, Lila Missae; Caperuto, Érico Chagas; de Souza, Cláudio Teodoro; Barboza, Catarina de Andrade; Rocha, Leandro Yanase; Figueroa, Diego; Mostarda, Cristiano; Irigoyen, Maria Cláudia; Lira, Fábio Santos

2014-01-01

The aim of this study was to evaluate the effects of exercise training (ET, 50-70% of VO2 max, 5 days/week) and detraining (DT) on inflammatory and metabolic profile after myocardial infarction (MI) in rats. Male Wistar rats were divided into control (C, n = 8), sedentary infarcted (SI, n = 9), trained infarcted (TI, n = 10; 3 months of ET), and detrained infarcted (DI, n = 11; 2 months of ET + 1 month of DT). After ET and DT protocols, ventricular function and inflammation, cardiovascular autonomic modulation (spectral analysis), and adipose tissue inflammation and lipolytic pathway were evaluated. ET after MI improved cardiac and vascular autonomic modulation, and these benefits were correlated with reduced inflammatory cytokines on the heart and adipose tissue. These positive changes were sustained even after 1 month of detraining. No expressive changes were observed in oxidative stress and lipolytic pathway in experimental groups. In conclusion, our results strongly suggest that the autonomic improvement promoted by ET, and maintained even after the detraining period, was associated with reduced inflammatory profile in the left ventricle and adipose tissue of rats subjected to MI. These data encourage enhancing cardiovascular autonomic function as a therapeutic strategy for the treatment of inflammatory process triggered by MI.

Role of Training and Detraining on Inflammatory and Metabolic Profile in Infarcted Rats: Influences of Cardiovascular Autonomic Nervous System

PubMed Central

Santana, Aline Alves; Santamarina, Aline Boveto; Oyama, Lila Missae; Caperuto, Érico Chagas; de Souza, Cláudio Teodoro; Barboza, Catarina de Andrade; Rocha, Leandro Yanase; Figueroa, Diego; Mostarda, Cristiano; Irigoyen, Maria Cláudia; Lira, Fábio Santos

2014-01-01

The aim of this study was to evaluate the effects of exercise training (ET, 50–70% of VO2 max, 5 days/week) and detraining (DT) on inflammatory and metabolic profile after myocardial infarction (MI) in rats. Male Wistar rats were divided into control (C, n = 8), sedentary infarcted (SI, n = 9), trained infarcted (TI, n = 10; 3 months of ET), and detrained infarcted (DI, n = 11; 2 months of ET + 1 month of DT). After ET and DT protocols, ventricular function and inflammation, cardiovascular autonomic modulation (spectral analysis), and adipose tissue inflammation and lipolytic pathway were evaluated. ET after MI improved cardiac and vascular autonomic modulation, and these benefits were correlated with reduced inflammatory cytokines on the heart and adipose tissue. These positive changes were sustained even after 1 month of detraining. No expressive changes were observed in oxidative stress and lipolytic pathway in experimental groups. In conclusion, our results strongly suggest that the autonomic improvement promoted by ET, and maintained even after the detraining period, was associated with reduced inflammatory profile in the left ventricle and adipose tissue of rats subjected to MI. These data encourage enhancing cardiovascular autonomic function as a therapeutic strategy for the treatment of inflammatory process triggered by MI. PMID:25045207

Interactions between muscle and the immune system during modified musculoskeletal loading

NASA Technical Reports Server (NTRS)

Tidball, James G.

2002-01-01

Interactions between the immune system and skeletal muscle may play a significant role in modulating the course of muscle injury and repair after modified musculoskeletal loading. Current evidence indicates that activation of the complement system is an early event during modified loading, which then leads to inflammatory cell invasion. However, the functions of those inflammatory cells are complex and they seem to be capable of promoting additional injury and repair. Recent findings implicate an early invading neutrophil population in increasing muscle damage that is detected by the presence of muscle membrane lesions. Macrophages that invade subsequently serve to remove cellular debris, and seem to promote repair. However, macrophages also have the ability to increase damage in muscle in which there is an impaired capacity to generate nitric oxide. In vivo and in vitro evidence indicates that muscle-derived nitric oxide can serve an important role in protecting muscle from membrane damage by invading inflammatory cells. Collectively, these findings indicate that the dynamic balance between inflammatory cells, the complement system, and muscle-derived free radicals can play important roles in the secondary damage of muscle during modified musculoskeletal loading.

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases

PubMed Central

Bencherif, Merouane; Lippiello, Patrick M.; Lucas, Rudolf; Marrero, Mario B.

2013-01-01

In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components. PMID:20953658

Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation

PubMed Central

Wright, K L; Duncan, M; Sharkey, K A

2007-01-01

The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction. PMID:17906675

Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice.

PubMed

Paouri, Evi; Tzara, Ourania; Kartalou, Georgia-Ioanna; Zenelak, Sofia; Georgopoulos, Spiros

2017-05-17

Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in β-amyloid clearance. SIGNIFICANCE STATEMENT Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a pluripotent cytokine that has been independently involved in the pathogenesis of systemic inflammatory rheumatoid arthritis (RA) and AD. Here we first demonstrate that manipulation of peripheral TNF-α in the context of arthritis modulates the amyloid phenotype by regulating immune cell trafficking in the mouse brain. Our study suggests that additionally to its local actions in the AD brain, TNF-α can also indirectly modulate amyloid pathology as a regulator of peripheral inflammation. Our findings may have significant implications in the treatment of RA patients with anti-TNF-α drugs and in the potential use of TNF-targeted therapies for AD. Copyright © 2017 the authors 0270-6474/17/375155-17$15.00/0.

Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction

PubMed Central

Chen, Yeong-Chang; Wei, Tsui-Shan; Sun, Ding-Ping; Wang, Jhi-Joung; Yeh, Ching-Hua

2015-01-01

Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1β in the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression. PMID:26273133

Surfactant protein A is expressed in the central nervous system of rats with experimental autoimmune encephalomyelitis, and suppresses inflammation in human astrocytes and microglia

PubMed Central

Yang, Xue; Yan, Jun; Feng, Juan

2017-01-01

The collectin surfactant protein-A (SP-A), a potent host defense molecule, is well recognized for its role in the maintenance of pulmonary homeostasis and the modulation of inflammatory responses. While previous studies have detected SP-A in numerous extrapulmonary tissues, there is still a lack of information regarding its expression in central nervous system (CNS) and potential effects in neuroinflammatory diseases, such as multiple sclerosis (MS). The present study used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS, to investigate the expression of SP-A in the CNS at different stages of disease progression. In addition, in vitro experiments with lipopolysaccharide (LPS)-stimulated human astrocytes and microglia were performed to investigate the potential role of SP-A in the modulation of CNS inflammatory responses. The results of the present study demonstrated widespread distribution of SP-A in the rat CNS, and also identified specific expression patterns of SP-A at different stages of EAE. In vitro, the current study revealed that treatment of human astrocytes and microglia with LPS promoted SP-A expression in a dose-dependent manner. Furthermore, exogenous SP-A protein significantly decreased Toll-like receptor 4 and nuclear factor-κB expression, and reduced interleukin-1β and tumor necrosis factor-α levels. The results of the current study indicate a potential role for SP-A in the modulation of CNS inflammatory responses. PMID:28393255

HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases

PubMed Central

Montgomery, McKale R.; Leyva, Kathryn J.

2016-01-01

Histone deacetylase (HDAC) inhibitors are powerful epigenetic regulators that have enormous therapeutic potential and have pleiotropic effects at the cellular and systemic levels. To date, HDAC inhibitors are used clinically for a wide variety of disorders ranging from hematopoietic malignancies to psychiatric disorders, are known to have anti-inflammatory properties, and are in clinical trials for several other diseases. In addition to influencing gene expression, HDAC enzymes also function as part of large, multisubunit complexes which have many nonhistone targets, alter signaling at the cellular and systemic levels, and result in divergent and cell-type specific effects. Thus, the effects of HDAC inhibitor treatment are too intricate to completely understand with current knowledge but the ability of HDAC inhibitors to modulate the immune system presents intriguing therapeutic possibilities. This review will explore the complexity of HDAC inhibitor treatment at the cellular and systemic levels and suggest strategies for effective use of HDAC inhibitors in biomedical research, focusing on the ability of HDAC inhibitors to modulate the immune system. The possibility of combining the documented anticancer effects and newly emerging immunomodulatory effects of HDAC inhibitors represents a promising new combinatorial therapeutic approach for HDAC inhibitor treatments. PMID:27556043

Interrelationship between Periapical Lesion and Systemic Metabolic Disorders

PubMed Central

Sasaki, Hajime; Hirai, Kimito; Martins, Christine Men; Furusho, Hisako; Battaglino, Ricardo; Hashimoto, Koshi

2016-01-01

Periapical periodontitis, also known as periapical lesion, is a common dental disease, along with periodontitis (gum disease). Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a “metabolically-triggered” low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. The host immune system is therefore considered the common fundamental mechanism of both disease conditions. An elevated inflammatory state caused by metabolic disorders can impact the clinical outcome of periapical lesions and interfere with wound healing after endodontic treatment. Although additional well-designed clinical studies are needed, periapical lesions appear to affect insulin sensitivity and exacerbate non-alcoholic steatohepatitis. Immune regulatory cytokines produced by various cell types, including immune cells and adipose tissue, play an important role in this interrelationship. PMID:26881444

Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

PubMed

Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

2008-06-01

Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

Features of anti-inflammatory effects of modulated extremely high-frequency electromagnetic radiation.

PubMed

Gapeyev, Andrew B; Mikhailik, Elena N; Chemeris, Nikolay K

2009-09-01

Using a model of acute zymosan-induced paw edema in NMRI mice, we test the hypothesis that anti-inflammatory effects of extremely high-frequency electromagnetic radiation (EHF EMR) can be essentially modified by application of pulse modulation with certain frequencies. It has been revealed that a single exposure of animals to continuous EHF EMR for 20 min reduced the exudative edema of inflamed paw on average by 19% at intensities of 0.1-0.7 mW/cm(2) and frequencies from the range of 42.2-42.6 GHz. At fixed effective carrier frequency of 42.2 GHz, the anti-inflammatory effect of EHF EMR did not depend on modulation frequencies, that is, application of different modulation frequencies from the range of 0.03-100 Hz did not lead to considerable changes in the effect level. On the contrary, at "ineffective" carrier frequencies of 43.0 and 61.22 GHz, the use of modulation frequencies of 0.07-0.1 and 20-30 Hz has allowed us to restore the effect up to a maximal level. The results obtained show the critical dependence of anti-inflammatory action of low-intensity EHF EMR on carrier and modulation frequencies. Within the framework of this study, the possibility of changing the level of expected biological effect of modulated EMR by a special selection of combination of carrier and modulation frequencies is confirmed.

Impact of exercise training associated to pyridostigmine treatment on autonomic function and inflammatory profile after myocardial infarction in rats.

PubMed

Feriani, Daniele J; Souza, Gabriel I H; Carrozzi, Nicolle M; Mostarda, Cristiano; Dourado, Paulo M M; Consolim-Colombo, Fernanda M; De Angelis, Kátia; Moreno, Heitor; Irigoyen, Maria Cláudia; Rodrigues, Bruno

2017-01-15

The effects of exercise training (ET) associated with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on inflammatory profile after myocardial infarction (MI), are unclear. Male Wistar rats were randomly assigned to: control (C); sedentary+infarcted (I); sedentary+infarcted treated with PYR (IP); infarcted submitted to aerobic exercise training (IT); and infarcted submitted to treatment with PYR and aerobic exercise training (ITP). After 12weeks of ET (50-70% maximal running speed; 1h a day, 5days a week) and/or PYR treatment (0.14mg/mL on drink water), hemodynamic, autonomic and cytokines expression were performed. We observed that both aerobic ET, associated or not with PYR treatment in MI animals, were able to: reduced MI area, improved systolic and diastolic function, baroreflex sensitivity, cardiovascular autonomic modulation, and tonic activity of the sympathetic and parasympathetic nervous system. Also, they led to a reduction of inflammatory profile measured at plasma, left ventricle and soleus skeletal muscle. However, additional effects were observed when ET and PYR were associated, such as an increase in vagal tonus and modulation, reduction of MI area, interferon-γ and tumor necrosis factor-α (TNF-α), as well as an increase of interleukin-10/TNF-α ratio on left ventricle. These data suggest that associating ET and PYR promotes some additional benefits on cardiovascular autonomic modulation and inflammatory profile in infarcted rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Thalidomide decreases the plasma levels of IL-1 and TNF following burn injury: is it a new drug for modulation of systemic inflammatory response.

PubMed

Eski, Muhitdin; Sahin, Ismail; Sengezer, Mustafa; Serdar, Muhittin; Ifran, Ahmet

2008-02-01

TNF and IL-1, which are produced from phagocytic cells, can produce a significant systemic inflammatory response independently by inducing systemic leukocyte and endothelial cell activation. These cytokines play a pivotal role in development of systemic inflammatory response after severe burn. Thalidomide has been shown to decrease the secretion of TNF from phagocytic cells, therefore suppression of TNF and IL-1 production from activated phagocytic cells might be a successful treatment modality for prevention of systemic inflammatory response following severe burn. To address this issue, we aimed to show whether thalidomide treatment decreased or suppressed plasma levels of TNF and IL-1 following burn in rats. Following the injury, 36 rats were randomly separated into two experimental groups at the third and seventh days. Rats in the experimental group had oral thalidomide (10mg/kg day) treatment for three and seven consecutive days whereas animals in control groups had no treatment. Thalidomide treatment decreased TNF and IL-1 significantly in both experimental groups at both the points (P<0.05). Although in this study we just showed inhibitory effect of thalidomide on plasma the level of TNF and IL-1, we speculate that thalidomide may have modulatory effect on the systemic inflammatory response after burn by decreasing plasma levels of TNF and IL-1.

An integrative view of microbiome-host interactions in inflammatory bowel diseases

PubMed Central

Wlodarska, Marta; Kostic, Aleksandar D.; Xavier, Ramnik J.

2015-01-01

Summary The intestinal microbiota, which is composed of bacteria, viruses, and micro-eukaryotes, acts as an accessory organ system with distinct functions along the intestinal tract that are critical for health. This review focuses on how the microbiota drives intestinal disease through alterations in microbial community architecture, disruption of the mucosal barrier, modulation of innate and adaptive immunity, and dysfunction of the enteric nervous system. Inflammatory bowel disease is used as a model system to understand these microbial-driven pathologies, but the knowledge gained in this space is extended to less well studied intestinal diseases that may also have an important microbial component, including environmental enteropathy and chronic colitis-associated colorectal cancer. PMID:25974300

Modulation of CD11c+ lung dendritic cells in respect to TGF-β in experimental pulmonary fibrosis.

PubMed

Chakraborty, Kaustav; Chatterjee, Soumya; Bhattacharyya, Arindam

2017-09-01

Idiopathic pulmonary fibrosis (IPF) is a deadly, progressive lung disease with very few treatment options till now. Bleomycin-induced pulmonary fibrosis (BIPF) is a commonly used mice model in IPF research. TGF-β1 has been shown to play a key role in pulmonary fibrosis (PF). Dendritic cell (DC) acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of pulmonary fibrosis. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to TGF-β in PF. First, we established BIPF model in mice and blocked TGF-β expression by the use of inhibitor SB431542. Accumulation of lung CD11c+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of TGF-β. TGF-β initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset CD11c+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of BIPF. Blocking of TGF-β causes decreased expression of CD11c+CD103+ DCs. Another important lung DC subset CD11c+CD11b+ expression is suppressed by the absence of TGF-β after bleomycin administration. CD11c+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of CD11c+ lung DCs by TGF-β in experimental PF. © 2017 International Federation for Cell Biology.

Advances in cholangiocyte immunobiology

PubMed Central

Syal, Gaurav; Fausther, Michel

2012-01-01

Cholangiocytes, or bile duct epithelia, were once thought to be the simple lining of the conduit system comprising the intra- and extrahepatic bile ducts. Growing experimental evidence demonstrated that cholangiocytes are in fact the first line of defense of the biliary system against foreign substances. Experimental advances in recent years have unveiled previously unknown roles of cholangiocytes in both innate and adaptive immune responses. Cholangiocytes can release inflammatory modulators in a regulated fashion. Moreover, they express specialized pattern-recognizing molecules that identify microbial components and activate intracellular signaling cascades leading to a variety of downstream responses. The cytokines secreted by cholangiocytes, in conjunction with the adhesion molecules expressed on their surface, play a role in recruitment, localization, and modulation of immune responses in the liver and biliary tract. Cholangiocyte survival and function is further modulated by cytokines and inflammatory mediators secreted by immune cells and cholangiocytes themselves. Because cholangiocytes act as professional APCs via expression of major histocompatibility complex antigens and secrete antimicrobial peptides in bile, their role in response to biliary infection is critical. Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis. PMID:22961800

Advances in cholangiocyte immunobiology.

PubMed

Syal, Gaurav; Fausther, Michel; Dranoff, Jonathan A

2012-11-15

Cholangiocytes, or bile duct epithelia, were once thought to be the simple lining of the conduit system comprising the intra- and extrahepatic bile ducts. Growing experimental evidence demonstrated that cholangiocytes are in fact the first line of defense of the biliary system against foreign substances. Experimental advances in recent years have unveiled previously unknown roles of cholangiocytes in both innate and adaptive immune responses. Cholangiocytes can release inflammatory modulators in a regulated fashion. Moreover, they express specialized pattern-recognizing molecules that identify microbial components and activate intracellular signaling cascades leading to a variety of downstream responses. The cytokines secreted by cholangiocytes, in conjunction with the adhesion molecules expressed on their surface, play a role in recruitment, localization, and modulation of immune responses in the liver and biliary tract. Cholangiocyte survival and function is further modulated by cytokines and inflammatory mediators secreted by immune cells and cholangiocytes themselves. Because cholangiocytes act as professional APCs via expression of major histocompatibility complex antigens and secrete antimicrobial peptides in bile, their role in response to biliary infection is critical. Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis.

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

18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

PubMed

Zhou, Jieru; Cai, Wei; Jin, Min; Xu, Jingwei; Wang, Yanan; Xiao, Yichuan; Hao, Li; Wang, Bei; Zhang, Yanyun; Han, Jie; Huang, Rui

2015-09-02

Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.

Anti-Inflammatory Nutrition as a Pharmacological Approach to Treat Obesity

PubMed Central

Sears, Barry; Ricordi, Camillo

2011-01-01

Obesity is a multifactorial condition resulting from improper balances of hormones and gene expression induced by the diet. Obesity also has a strong inflammatory component that can be driven by diet-induced increases in arachidonic acid. The purpose of this paper is to discuss the molecular targets that can be addressed by anti-inflammatory nutrition. These molecular targets range from reduction of proinflammatory eicosanoids to the modulation of features of the innate immune system, such as toll-like receptors and gene transcription factors. From knowledge of the impact of these dietary nutrients on these various molecular targets, it becomes possible to develop a general outline of an anti-inflammatory diet that can offer a unique synergism with more traditional pharmacological approaches in treating obesity and its associated comorbidities. PMID:20953366

Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy – a case report

PubMed Central

Tomescu, Dana; Dima, Simona O.; Tănăsescu, Sabina; Tănase, Cristiana Pistol; Năstase, Anca; Popescu, Mihai

2014-01-01

Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb®) in combination with continuous veno-venous haemofiltration was associated with a decrease in TNFα, IL-1β and IFNγ and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb® on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb® and to evaluate the overall outcome. PMID:28913446

Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy - a case report.

PubMed

Tomescu, Dana; Dima, Simona O; Tănăsescu, Sabina; Tănase, Cristiana Pistol; Năstase, Anca; Popescu, Mihai

2014-10-01

Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb ® ) in combination with continuous veno-venous haemofiltration was associated with a decrease in TNFα, IL-1β and IFNγ and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb ® on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb ® and to evaluate the overall outcome.

Gut REG3γ-Associated Lactobacillus Induces Anti-inflammatory Macrophages to Maintain Adipose Tissue Homeostasis

PubMed Central

Huang, Yugang; Qi, HouBao; Zhang, Zhiqian; Wang, Enlin; Yun, Huan; Yan, Hui; Su, Xiaomin; Liu, Yingquan; Tang, Zenzen; Gao, Yunhuan; Shang, Wencong; Zhou, Jiang; Wang, Tianze; Che, Yongzhe; Zhang, Yuan; Yang, Rongcun

2017-01-01

Gut microbiota may not only affect composition of local immune cells but also affect systemic immune cells. However, it is not completely clear how gut microbiota modulate these immune systems. Here, we found that there exist expanded macrophage pools in huREG3γtgIEC mice. REG3γ-associated Lactobacillus, which is homology to Lactobacillus Taiwanese, could enlarge macrophage pools not only in the small intestinal lamina propria but also in the spleen and adipose tissues. STAT3-mediated signal(s) was a critical factor in the Lactobacillus-mediated anti-inflammatory macrophages. We also offered evidence for critical cellular links among REG3γ-associated Lactobacillus, tissue macrophages, and obesity diseases. Anti-inflammatory macrophages in the lamina propria, which are induced by REG3γ-associated Lactobacillus, may migrate into adipose tissues and are involved in resistance against high-fat diet-mediated obesity. Thus, REG3γ-associated Lactobacillus-induced anti-inflammatory macrophages in gut tissues may play a role in adipose tissue homeostasis. PMID:28928739

In vitro anti-inflammatory activity of selected oxalate-degrading probiotic bacteria: potential applications in the prevention and treatment of hyperoxaluria.

PubMed

Giardina, Silvana; Scilironi, Cristina; Michelotti, Angela; Samuele, Alberta; Borella, Fabio; Daglia, Maria; Marzatico, Fulvio

2014-03-01

Oxalate (Ox) is a very common component of the human diet, capable to collect in the renal tissue and bind calcium to form calcium oxalate (CaOx) crystals. A supersaturation of CaOx crystal may cause nephrocalcinosis and nephrolithiasis. The inflammation derived from the CaOx crystal accumulation, together with innate or secondary renal alterations, could strongly affect the renal function. In this case a consumption of probiotics with either oxalate-degrading activity at intestinal level and systemic anti-inflammatory activity could be an alternative approach to treat the subjects with excess of urinary oxalate excretion. 11 strains of lactic acid bacteria (Lactobacilli and Bifidobacteria), already included in the list of bacteria safe for the human use, were investigated for their capability to degrade oxalate by mean of RP-HPLC-UV method and modulate inflammation in an in vitro model system based on peripheral blood mononuclear cells. Four promising bacterial strains (Lactobacillus plantarum PBS067, Lactobacillus acidophilus LA-14, Bifidobacterium breve PBS077, Bifidobacterium longum PBS078) were identified as innovative biological tools for the prevention and the therapeutic treatment of hyperoxaluria and the inflammatory events associated to the Ox accumulation. The oxalate-degrading activity of some probiotics and their capability to modulate the release of inflammation mediators could be exploited as a new nutraceutical and therapeutic approach for the treatment of oxalate accumulation and the related inflammatory state. © 2014 Institute of Food Technologists®

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

Zinc in Infection and Inflammation

PubMed Central

Gammoh, Nour Zahi; Rink, Lothar

2017-01-01

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli. PMID:28629136

Zinc in Infection and Inflammation.

PubMed

Gammoh, Nour Zahi; Rink, Lothar

2017-06-17

Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-κB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli.

Probiotic Modulation of Innate Cell Pathogen Sensing and Signaling Events

PubMed Central

Llewellyn, Amy; Foey, Andrew

2017-01-01

There is a growing body of evidence documenting probiotic bacteria to have a beneficial effect to the host through their ability to modulate the mucosal immune system. Many probiotic bacteria can be considered to act as either immune activators or immune suppressors, which have appreciable influence on homeostasis, inflammatory- and suppressive-immunopathology. What is becoming apparent is the ability of these probiotics to modulate innate immune responses via direct or indirect effects on the signaling pathways that drive these activatory or suppressive/tolerogenic mechanisms. This review will focus on the immunomodulatory role of probiotics on signaling pathways in innate immune cells: from positive to negative regulation associated with innate immune cells driving gut mucosal functionality. Research investigations have shown probiotics to modulate innate functionality in many ways including, receptor antagonism, receptor expression, binding to and expression of adaptor proteins, expression of negative regulatory signal molecules, induction of micro-RNAs, endotoxin tolerisation and finally, the secretion of immunomodulatory proteins, lipids and metabolites. The detailed understanding of the immunomodulatory signaling effects of probiotic strains will facilitate strain-specific selective manipulation of innate cell signal mechanisms in the modulation of mucosal adjuvanticity, immune deviation and tolerisation in both healthy subjects and patients with inflammatory and suppressive pathology. PMID:29065562

Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential.

PubMed

Spitz, Charlotte; Winkels, Holger; Bürger, Christina; Weber, Christian; Lutgens, Esther; Hansson, Göran K; Gerdes, Norbert

2016-03-01

Atherosclerosis is a chronic inflammatory disease that is mediated by innate and adaptive immune responses. The disease is characterized by sub-endothelial accumulation and modification of lipids in the artery wall triggering an inflammatory reaction which promotes lesion progression and eventual plaque rupture, thrombus formation, and the respective clinical sequelae such as myocardial infarction or stroke. During the past decade, T-cell-mediated immune responses, especially control of pro-inflammatory signals by regulatory T cells (Tregs), have increasingly attracted the interest of experimental and clinical researchers. By suppression of T cell proliferation and secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β, Tregs exert their atheroprotective properties. Atherosclerosis-prone, hyperlipidemic mice harbor systemically less Tregs compared to wild-type mice, suggesting an imbalance of immune cells which affects local and systemic inflammatory and potentially metabolic processes leading to atherogenesis. Restoring or increasing Treg frequency and enhancing their suppressive capacity by various modulations may pose a promising approach for treating inflammatory conditions such as cardiovascular diseases. In this review, we briefly summarize the immunological basics of atherosclerosis and introduce the role and contribution of different subsets of T cells. We then discuss experimental data and current knowledge pertaining to Tregs in atherosclerosis and perspectives on manipulating the adaptive immune system to alleviate atherosclerosis and cardiovascular disease.

Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER

PubMed Central

Lv, Qiao-Ying; Xie, Bing-Ying; Yang, Bing-Yi; Ning, Cheng-Cheng; Shan, Wei-Wei; Gu, Chao; Luo, Xue-Zhen; Chen, Xiao-Jun; Zhang, Zhen-Bo; Feng, You-Ji

2017-01-01

Background: Insulin resistance (IR) has been well studied in the initiation and development of endometrial endometrioid carcinoma (EEC). As yet, it has been largely neglected for estrogen sensitivity in local endometrium in hyperinsulinemia-induced systemic microenvironment. The aim of this study was to investigate the role of insulin in regulating estrogen sensitivity and explore the potential mechanisms in insulin-driven inflammatory microenvironment. Methods: We first investigated the effect of insulin on estradiol-driven endometrial cancer cells proliferation in vitro to address the roles of insulin in modulating estrogen sensitivity. Then GPER, ERα and TET1 in EEC samples with or without insulin resistance were screened by immunohistochemistry to confirm whether insulin resistance regulates estrogen receptors. Further mechanism analysis was carried out to address whether TET1 was mediated epigenetic modulation of GPER in insulin-induced microenvironment. Results: Insulin enhanced estradiol-driven endometrial cancer cells proliferation by up-regulating G-protein-coupled estrogen receptor (GPER) expression, but not ERα or ERβ. Immunohistochemistry of EEC tissues showed that GPER expression was greatly increased in endometrial tissues from EEC subjects with insulin resistance and was positively correlated with Ten-eleven-translocation 1 (TET1) expression. Mechanistically, insulin up-regulates TET1 expression, and the latter, an important DNA hydroxymethylase, could up-regulate GPER expression through epigenetic modulation. Conclusion: This study identified TET1 as the upstream regulator of GPER expression and provides a possible mechanism that insulin-induced positive regulation of estrogen sensitivity in endometrial cancer cells. Increasing expression of GPER through TET1-mediated epigenetic modulation may emerge as the main regulator to enhance the response of endometrial cancer to estrogen in insulin-driven inflammatory microenvironment. PMID:28382153

Increased TET1 Expression in Inflammatory Microenvironment of Hyperinsulinemia Enhances the Response of Endometrial Cancer to Estrogen by Epigenetic Modulation of GPER.

PubMed

Lv, Qiao-Ying; Xie, Bing-Ying; Yang, Bing-Yi; Ning, Cheng-Cheng; Shan, Wei-Wei; Gu, Chao; Luo, Xue-Zhen; Chen, Xiao-Jun; Zhang, Zhen-Bo; Feng, You-Ji

2017-01-01

Background: Insulin resistance (IR) has been well studied in the initiation and development of endometrial endometrioid carcinoma (EEC). As yet, it has been largely neglected for estrogen sensitivity in local endometrium in hyperinsulinemia-induced systemic microenvironment. The aim of this study was to investigate the role of insulin in regulating estrogen sensitivity and explore the potential mechanisms in insulin-driven inflammatory microenvironment. Methods: We first investigated the effect of insulin on estradiol-driven endometrial cancer cells proliferation in vitro to address the roles of insulin in modulating estrogen sensitivity. Then GPER, ERα and TET1 in EEC samples with or without insulin resistance were screened by immunohistochemistry to confirm whether insulin resistance regulates estrogen receptors. Further mechanism analysis was carried out to address whether TET1 was mediated epigenetic modulation of GPER in insulin-induced microenvironment. Results: Insulin enhanced estradiol-driven endometrial cancer cells proliferation by up-regulating G-protein-coupled estrogen receptor (GPER) expression, but not ERα or ERβ. Immunohistochemistry of EEC tissues showed that GPER expression was greatly increased in endometrial tissues from EEC subjects with insulin resistance and was positively correlated with Ten-eleven-translocation 1 (TET1) expression. Mechanistically, insulin up-regulates TET1 expression, and the latter, an important DNA hydroxymethylase, could up-regulate GPER expression through epigenetic modulation. Conclusion: This study identified TET1 as the upstream regulator of GPER expression and provides a possible mechanism that insulin-induced positive regulation of estrogen sensitivity in endometrial cancer cells. Increasing expression of GPER through TET1-mediated epigenetic modulation may emerge as the main regulator to enhance the response of endometrial cancer to estrogen in insulin-driven inflammatory microenvironment.

Impact of antibiotics on the microcirculation in local and systemic inflammation.

PubMed

Al-Banna, N A; Pavlovic, D; Gründling, M; Zhou, J; Kelly, M; Whynot, S; Hung, O; Johnston, B; Issekutz, T B; Kern, H; Cerny, V; Lehmann, Ch

2013-01-01

The main function of antibiotics is related to their capacity to eliminate a microorganism. In addition to the antimicrobial function of antibiotics, they are known to have anti-inflammatory and vasomodulatory effects on the microcirculation. The ability of non-antimicrobial derivatives of antibiotics to control inflammation illustrates the distinct anti-microbial and anti-inflammatory roles of antibiotics. In this review, we discuss the impact of antibiotics on leukocyte recruitment and the state of the microcirculation. Literature reporting the effect of antibiotics in non-infectious inflammatory conditions is reviewed as well as the studies demonstrating the anti-inflammatory effects of antibiotics in animal models of infection. In addition, the effect of the antibiotics on the immune system is summarized in this review, in order to postulate some mechanisms of action for the proand anti-inflammatory contribution of antibiotics. Literature reported the effect of antibiotics on the production of cytokines, chemotaxis and recruitment of leukocytes, production of reactive oxygen species, process of phagocytosis and autophagy, and apoptosis of leukocytes. Yet, all antibiotics may not necessarily exert an anti-inflammatory effect on the microcirculation. Thus, we suggest a model for spectrum of anti-inflammatory and vasomodulatory effects of antibiotics in the microcirculation of animals in local and systemic inflammation. Although the literature suggests the ability of antibiotics to modulate leukocyte recruitment and microperfusion, the process and the mechanism of action are not fully characterized. Studying this process will expand the knowledge base that is required for the selection of antibiotic treatment based on its anti-inflammatory functions, which might be particularly important for critically ill patients.

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I

PubMed Central

Vieira, Graziela; Cavalli, Juliana; Gonçalves, Elaine C. D.; Gonçalves, Tainara R.; Laurindo, Larissa R.; Cola, Maíra; Dutra, Rafael C.

2017-01-01

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I. PMID:28928655

Integrin-directed modulation of macrophage responses to biomaterials.

PubMed

Zaveri, Toral D; Lewis, Jamal S; Dolgova, Natalia V; Clare-Salzler, Michael J; Keselowsky, Benjamin G

2014-04-01

Macrophages are the primary mediator of chronic inflammatory responses to implanted biomaterials, in cases when the material is either in particulate or bulk form. Chronic inflammation limits the performance and functional life of numerous implanted medical devices, and modulating macrophage interactions with biomaterials to mitigate this response would be beneficial. The integrin family of cell surface receptors mediates cell adhesion through binding to adhesive proteins nonspecifically adsorbed onto biomaterial surfaces. In this work, the roles of integrin Mac-1 (αMβ2) and RGD-binding integrins were investigated using model systems for both particulate and bulk biomaterials. Specifically, the macrophage functions of phagocytosis and inflammatory cytokine secretion in response to a model particulate material, polystyrene microparticles were investigated. Opsonizing proteins modulated microparticle uptake, and integrin Mac-1 and RGD-binding integrins were found to control microparticle uptake in an opsonin-dependent manner. The presence of adsorbed endotoxin did not affect microparticle uptake levels, but was required for the production of inflammatory cytokines in response to microparticles. Furthermore, it was demonstrated that integrin Mac-1 and RGD-binding integrins influence the in vivo foreign body response to a bulk biomaterial, subcutaneously implanted polyethylene terephthalate. A thinner foreign body capsule was formed when integrin Mac-1 was absent (~30% thinner) or when RGD-binding integrins were blocked by controlled release of a blocking peptide (~45% thinner). These findings indicate integrin Mac-1 and RGD-binding integrins are involved and may serve as therapeutic targets to mitigate macrophage inflammatory responses to both particulate and bulk biomaterials. Copyright © 2014 Elsevier Ltd. All rights reserved.

Strain-dependent release of cytokines modulated by Lactobacillus salivarius human isolates in an in vitro model

PubMed Central

2010-01-01

Background Oral administration of probiotics is known to modulate cytokines profile not only locally, but also systemically. Four strains of Lactobacillus salivarius, LDR0723, BNL1059, RGS1746 and CRL1528, were evaluated for their ability to modulate release of pro- and anti-inflammatory cytokines. Findings Strains were assessed for effects on production of Interleukin-12 (IL-12), Interferon-γ (IFN-γ), Interleukin-4 (IL-4) and Interleukin-5 (IL-5) by incubating bacterial suspensions with THP-1 macrophage like cells. Cytokines were determined by means of specific quantitative enzyme-linked immunosorbent assays. LDR0723 and CRL1528 led to a sustained increment in production of IL-12 and IFN-γ and to a decrease in release of IL-4 and IL-5, while BNL1059 and RGS1746 favoured Th2 response, leading to a decrease in Th1/Th2 ratio with respect to unstimulated cells. Conclusions In conclusion, capability of L. salivarius to modulate immune response was strictly strain dependent and strains of the same species might have opposite effects. Therefore, a careful evaluation of anti-inflammatory properties of lactobacilli should be performed on single strain, before any consideration on potential probiotic use. PMID:20184725

Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases.

PubMed

Escobar, Javier; Pereda, Javier; Arduini, Alessandro; Sandoval, Juan; Sabater, Luis; Aparisi, Luis; López-Rodas, Gerardo; Sastre, Juan

2009-01-01

Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homestasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways. This review focuses on the relationship between oxidative stress, pro-inflammatory cytokines and MAP kinase/protein phosphatase pathways as major modulators of the inflammatory response in acute pancreatitis. Redox sensitive signal transduction mediated by inactivation of protein phosphatases, particularly protein tyrosin phosphatases, is highlighted.

BID Mediates Oxygen-Glucose Deprivation-Induced Neuronal Injury in Organotypic Hippocampal Slice Cultures and Modulates Tissue Inflammation in a Transient Focal Cerebral Ischemia Model without Changing Lesion Volume

PubMed Central

Martin, Nellie Anne; Bonner, Helena; Elkjær, Maria Louise; D’Orsi, Beatrice; Chen, Gang; König, Hans Georg; Svensson, Martina; Deierborg, Tomas; Pfeiffer, Shona; Prehn, Jochen H.; Lambertsen, Kate Lykke

2016-01-01

The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and wild type (WT) mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) to induce focal cerebral ischemia, and allowed to recover for 24 h. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR (qPCR) and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo. PMID:26869884

The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

PubMed

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-05-09

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

PubMed Central

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-01-01

Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

Expression and Function of the Cholinergic System in Immune Cells

PubMed Central

Fujii, Takeshi; Mashimo, Masato; Moriwaki, Yasuhiro; Misawa, Hidemi; Ono, Shiro; Horiguchi, Kazuhide; Kawashima, Koichiro

2017-01-01

T and B cells express most cholinergic system components—e.g., acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase, and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Using ChATBAC-eGFP transgenic mice, ChAT expression has been confirmed in T and B cells, dendritic cells, and macrophages. Moreover, T cell activation via T-cell receptor/CD3-mediated pathways upregulates ChAT mRNA expression and ACh synthesis, suggesting that this lymphocytic cholinergic system contributes to the regulation of immune function. Immune cells express all five mAChRs (M1–M5). Combined M1/M5 mAChR-deficient (M1/M5-KO) mice produce less antigen-specific antibody than wild-type (WT) mice. Furthermore, spleen cells in M1/M5-KO mice produce less tumor necrosis factor (TNF)-α and interleukin (IL)-6, suggesting M1/M5 mAChRs are involved in regulating pro-inflammatory cytokine and antibody production. Immune cells also frequently express the α2, α5, α6, α7, α9, and α10 nAChR subunits. α7 nAChR-deficient (α7-KO) mice produce more antigen-specific antibody than WT mice, and spleen cells from α7-KO mice produce more TNF-α and IL-6 than WT cells. This suggests that α7 nAChRs are involved in regulating cytokine production and thus modulate antibody production. Evidence also indicates that nicotine modulates immune responses by altering cytokine production and that α7 nAChR signaling contributes to immunomodulation through modification of T cell differentiation. Together, these findings suggest the involvement of both mAChRs and nAChRs in the regulation of immune function. The observation that vagus nerve stimulation protects mice from lethal endotoxin shock led to the notion of a cholinergic anti-inflammatory reflex pathway, and the spleen is an essential component of this anti-inflammatory reflex. Because the spleen lacks direct vagus innervation, it has been postulated that ACh synthesized by a subset of CD4+ T cells relays vagal nerve signals to α7 nAChRs on splenic macrophages, which downregulates TNF-α synthesis and release, thereby modulating inflammatory responses. However, because the spleen is innervated solely by the noradrenergic splenic nerve, confirmation of an anti-inflammatory reflex pathway involving the spleen requires several more hypotheses to be addressed. We will review and discuss these issues in the context of the cholinergic system in immune cells. PMID:28932225

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.

Recombinant Brugia malayi pepsin inhibitor (rBm33) exploits host signaling events to regulate inflammatory responses associated with lymphatic filarial infections.

PubMed

Sreenivas, Kirthika; Kalyanaraman, Haripriya; Babu, Subash; Narayanan, Rangarajan Badri

2017-11-01

Prolonged existence of filarial parasites and their molecules within the host modulate the host immune system to instigate their survival and induce inflammatory responses that contribute to disease progression. Recombinant Brugia malayi pepsin inhibitor (rBm33) modulates the host immune responses by skewing towards Th1 responses characterized by secretion of inflammatory molecules such as TNF-α, IL-6, nitric oxide (NO). Here we also specified the molecular signaling events triggered by rBm33 in peripheral blood mononuclear cells (PBMCs) of filarial endemic normals (EN). rBm33 predominantly enhanced the levels of nitric oxide in cultured PBMCs but did not result in oxidative stress to the host cells. Further, rBm33 treatment of human PBMCs resulted in higher GSH/GSSG levels. MYD88 dependent activation was found to be associated with rBm33 specific inflammatory cytokine production. rBm33 triggered intracellular signaling events also involved JNK activation in host PBMCs. In addition, c-Fos and not NF-κB was identified as the transcription factor regulating the expression of inflammatory cytokines in rBm33 stimulated PBMCs. rBm33 marked its role in filarial pathology by altered levels of growth factors but did not have a significant impact on matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs) activity of host PBMCs. Thus, the study outlines the signaling network of rBm33 induced inflammatory responses within the host immune cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

A Dialogue between the Immune System and Brain, Spoken in the Language of Serotonin

PubMed Central

2012-01-01

Neuropsychiatric disorders have long been linked to both immune system activation and alterations in serotonin (5-HT) signaling. In the CNS, the contributions of 5-HT modulate a broad range of targets, most notably, hypothalamic, limbic and cortical circuits linked to the control of mood and mood disorders. In the periphery, many are aware of the production and actions of 5-HT in the gut but are unaware that the molecule and its receptors are also present in the immune system where evidence suggests they contribute to the both innate and adaptive responses. In addition, there is clear evidence that the immune system communicates to the brain via both humoral and neuronal mechanisms, and that CNS 5-HT neurons are a direct or indirect target for these actions. Following a brief primer on the immune system, we describe our current understanding of the synthesis, release, and actions of 5-HT in modulating immune function, including the expression of 5-HT biosynthetic enzymes, receptors, and transporters that are typically studied with respect to the roles in the CNS. We then orient our presentation to recent findings that pro-inflammatory cytokines can modulate CNS 5-HT signaling, leading to a conceptualization that among the many roles of 5-HT in the body is an integrated physiological and behavioral response to inflammatory events and pathogens. From this perspective, altered 5-HT/immune conversations are likely to contribute to risk for neurobehavioral disorders historically linked to compromised 5-HT function or ameliorated by 5-HT targeted medications, including depression and anxiety disorders, obsessive-compulsive disorder (OCD), and autism. Our review raises the question as to whether genetic variation impacting 5-HT signaling genes may contribute to maladaptive behavior as much through perturbed immune system modulation as through altered brain mechanisms. Conversely, targeting the immune system for therapeutic development may provide an important opportunity to treat mental illness. PMID:23336044

Melatonin: Buffering the Immune System

PubMed Central

Carrillo-Vico, Antonio; Lardone, Patricia J.; Álvarez-Sánchez, Nuria; Rodríguez-Rodríguez, Ana; Guerrero, Juan M.

2013-01-01

Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. PMID:23609496

Roles of microRNA in the immature immune system of neonates.

PubMed

Yu, Hong-Ren; Huang, Lien-Hung; Li, Sung-Chou

2018-06-13

Neonates have an immature immune system; therefore, their immune activities are different from the activities of adult immune systems. Such differences between neonates and adults are reflected by cell population constitutions, immune responses, cytokine production, and the expression of cellular/humoral molecules, which contribute to the specific neonatal microbial susceptibility and atopic properties. MicroRNAs (miRNAs) have been discovered to modulate many aspects of immune responses. Herein, we summarize the distinct manifestations of the neonatal immune system, including cellular and non-cellular components. We also review the current findings on the modulatory effects of miRNAs on the neonatal immune system. These findings suggest that miRNAs have the potential to be useful therapeutic targets for certain infection or inflammatory conditions by modulating the neonatal immune system. In the future, we need a more comprehensive understanding in regard to miRNAs and how they modulate specific immune cells in neonates. Copyright © 2018. Published by Elsevier B.V.

Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice.

PubMed

Bagarolli, Renata A; Tobar, Natália; Oliveira, Alexandre G; Araújo, Tiago G; Carvalho, Bruno M; Rocha, Guilherme Z; Vecina, Juliana F; Calisto, Kelly; Guadagnini, Dioze; Prada, Patrícia O; Santos, Andrey; Saad, Sara T O; Saad, Mario J A

2017-12-01

Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

PubMed Central

Shah, Suharsh; Altonsy, Mohammed O.; Gerber, Antony N.

2017-01-01

Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid. PMID:28283576

RAR/RXR and PPAR/RXR Signaling in Spinal Cord Injury

PubMed Central

van Neerven, Sabien; Mey, Jörg

2007-01-01

The retinoid acid receptors (RAR) and peroxisome proliferator-activated receptors (PPAR) have been implicated in the regulation of inflammatory reactions. Both receptor families contain ligand-activated transcription factors which form heterodimers with retinoid X receptors (RXR). We review data that imply RAR/RXR and PPAR/RXR pathways in physiological reactions after spinal cord injury. Experiments show how RAR signaling may improve axonal regeneration and modulate reactions of glia cells. While anti-inflammatory properties of PPAR are well documented in the periphery, their possible roles in the central nervous system have only recently become evident. Due to its anti-inflammatory function this transcription factor family promises to be a useful target after spinal cord or brain lesions. PMID:18060014

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

PubMed Central

Lawton, Samira K.; Xu, Fengyun; Tran, Alphonso; Wong, Erika; Schumacher, Mark; Wilhelmsen, Kevin

2017-01-01

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA’s anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation. PMID:28701511

Lubricin: A Principal Modulator of the Psychoneuroendocrine - Osteoimmune Interactome - Implications for Novel Treatments of Osteoarthritic Pathologies.

PubMed

Khakshooy, Allen; Balenton, Nicole; Chiappelli, Francesco

2017-01-01

Lubricin is a synovial glycoprotein that contributes to joint lubrication. We propose the hypothesis that lubricin is a key modulator of the psychoneuroendocrine-osteoimmune interactome, with important clinical relevance for osteoarthritic pathologies. We consider a variety of neuroendocrine-immune factors, including inflammatory cytokines and chemokines that may contribute to the modulation of lubricin in rheumatic complications. Based on our preliminary immunocytochemistry and fractal analysis data, and in the context of translational research of modern healthcare, we propose that molecular lubricin gene expression modification by means of the novel CRISPR/Cas system be considered for osteoarthritic therapies.

Is lactate an undervalued functional component of fermented food products?

PubMed Central

Garrote, Graciela L.; Abraham, Analía G.; Rumbo, Martín

2015-01-01

Although it has been traditionally regarded as an intermediate of carbon metabolism and major component of fermented dairy products contributing to organoleptic and antimicrobial properties of food, there is evidence gathered in recent years that lactate has bioactive properties that may be responsible of broader properties of functional foods. Lactate can regulate critical functions of several key players of the immune system such as macrophages and dendritic cells, being able to modulate inflammatory activation of epithelial cells as well. Intraluminal levels of lactate derived from fermentative metabolism of lactobacilli have been shown to modulate inflammatory environment in intestinal mucosa. The molecular mechanisms responsible to these functions, including histone deacetylase dependent-modulation of gene expression and signaling through G-protein coupled receptors have started to be described. Since lactate is a major fermentation product of several bacterial families with probiotic properties, we here propose that it may contribute to some of the properties attributed to these microorganisms and in a larger view, to the properties of food products fermented by lactic acid bacteria. PMID:26150815

Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

USDA-ARS?s Scientific Manuscript database

Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

PubMed Central

Mountziaris, Paschalia M.; Spicer, Patrick P.; Kasper, F. Kurtis

2011-01-01

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID:21615330

Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

PubMed Central

2016-01-01

In the last decade, the immunomodulatory properties of mesenchymal stromal cells (MSCs) have attracted a lot of attention, due to their potential applicability in the treatment of graft-versus-host disease (GVHD), a condition frequently associated with opportunistic infections. The present review addresses how Pathogen-Associated Molecular Patterns (PAMPS) modulate the immunosuppressive phenotype of human MSCs by signaling through Toll-like receptors (TLRs). Overall, we observed that regardless of the source tissue, human MSCs express TLR2, TLR3, TLR4, and TLR9. Stimulation of distinct TLRs on MSCs elicits distinct inflammatory signaling pathways, differentially influencing the expression of inflammatory factors and the ability of MSCs to suppress the proliferation of immune system cells. The capacity to enhance the immunosuppressive phenotype of MSCs through TLRs stimulation might be properly elucidated in order to improve the MSC-based immunotherapy against GVHD. PMID:27738438

The therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: from preclinical studies to clinical trials.

PubMed

Bessaguet, Flavien; Magy, Laurent; Desmoulière, Alexis; Demiot, Claire

2016-01-01

The prevalence rate of chronic pain is 15% to 25% in adults while the therapeutic arsenal is still insufficient, especially in relieving neuropathic pain. Peripheral pain transmission is conducted by the small Aδ and C sensory nerve fibres. They express elements from the renin-angiotensin-aldosterone system (RAAS), a well-known blood pressure regulator. Recently, studies have demonstrated the role of angiotensin II, its derivatives and aldosterone in the modulation of pain perception, by interacting with receptors expressed by sensory nerve fibres or through the central nervous system. Here, we assess the effects of RAAS modulators in the conduction of pain with molecular, preclinical and clinical approaches, in normal or pathological conditions. Currently, some clinical studies have been carried out on the pain-relieving effect of RAAS modulators and suggest their potential in the management of chronic, inflammatory or neuropathic pain.

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

PubMed Central

Pohanka, Miroslav

2014-01-01

Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

PPARγ in Bacterial Infections: A Friend or Foe?

PubMed

Reddy, Aravind T; Lakshmi, Sowmya P; Reddy, Raju C

2016-01-01

Peroxisome proliferator-activated receptor γ (PPAR γ ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPAR γ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPAR γ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPAR γ and its activation during bacterial infections, with focus on the potential of PPAR γ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPAR γ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.

PPARγ in Bacterial Infections: A Friend or Foe?

PubMed Central

2016-01-01

Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system. PMID:27774097

The cholinergic anti-inflammatory pathway: An innovative treatment strategy for neurological diseases.

PubMed

Han, Bin; Li, Xiuping; Hao, Junwei

2017-06-01

Acetylcholine (ACh), as a classical neurotransmitter, regulates the neuronal network in response to internal and external stimuli. In recent decades, the biology of ACh has been endowed with unparalleled new insights, especially with respect to cholinergic anti-inflammatory properties in non-neuronal cells. In fact, a mechanism frequently referred to as the "cholinergic anti-inflammatory pathway" has been termed to describe interactions between the central nervous system (CNS) and the immune system via vagus nerve. As well documented, immune cells express choline acetyltransferase, a direct synthetase for ACh, and other corresponding cholinergic components. Alternatively, the ACh released from immune cells or cholinergic neurons modulates immune function in an autocrine/paracrine manner by acting on its receptors. Moreover, muscarinic or nicotinic ACh receptors on various immune cells and CNS glial cells administer the work of their respective agonists, causing functional and biochemical changes. In this review, we focus on the anti-inflammatory benefits of non-neuronal and neuronal ACh as a means of providing new insights into treating inflammation-related neurological diseases, as exemplified by those described herein. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ovocalyxin-36 is an effector protein modulating the production of proinflammatory mediators.

PubMed

Kovacs-Nolan, Jennifer; Cordeiro, Cristianne; Young, Denise; Mine, Yoshinori; Hincke, Maxwell

2014-07-15

Sepsis is a systemic inflammatory response syndrome during infection. Therapeutic agents are essential to protect the host from sepsis. Ovocalyxin-36 (OCX-36) is a chicken eggshell membrane protein and shares protein sequence and gene organization homology with bactericidal permeability-increasing protein (BPI), lipopolysaccharide-binding protein (LBP) and palate, lung and nasal epithelium clone (PLUNC) proteins that play a major role in innate immune protection. We recently reported that OCX-36 binds to both lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (Cordeiro et al., 2013, PLoS ONE 8, e84112), which is an important activity to neutralize endotoxins and non-endotoxin pyrogens during an inflammatory response. Here we investigated the immune modulating effects of OCX-36 and enzymatically digested OCX-36 (dOCX-36) in vitro and in a mouse model of endotoxemia. OCX-36 alone dose-dependently induced both TNF-α and nitric oxide (NO) production by RAW 264.7 macrophage cells, and this immunostimulatory effect was reduced by enzymatic digestion. In the presence of LPS, dOCX-36 was more effective than intact OCX-36 at reducing LPS-induced secretion of TNF-α from RAW 264.7 cells, but did not reduce NO production. In contrast, OCX-36 increased LPS-induced NO production, both in the presence and absence of FBS, PCR array analysis confirmed that OCX-36 and dOCX-36 differentially regulated genes involved in innate immunity, and dOCX-36 down-regulated the expression of genes involved in LPS signaling and inflammatory responses. In vivo, dOCX-36 was more effective at reducing LPS-induced inflammatory symptoms and inhibiting the local production of pro-inflammatory mediators in the small intestine. These results suggest that OCX-36 and OCX-36 derived peptides may differentially modulate innate immune responses, and support our hypothesis that OCX-36 derived peptides have potential therapeutic applications in sepsis. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Tolerogenic probiotics: potential immunoregulators in Systemic Lupus Erythematosus.

PubMed

Esmaeili, Seyed-Alireza; Mahmoudi, Mahmoud; Momtazi, Amir Abbas; Sahebkar, Amirhossein; Doulabi, Hassan; Rastin, Maryam

2017-08-01

Probiotics are commensal or nonpathogenic microbes that colonize the gastrointestinal tract and confer beneficial effects on the host through several mechanisms such as competitive exclusion, anti-bacterial effects, and modulation of immune responses. There is growing evidence supporting the immunomodulatory ability of some probiotics. Several experimental and clinical studies have been shown beneficial effect of some probiotic bacteria, particularly Lactobacillus and Bifidobacteria strains, on inflammatory and autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease that is mainly characterized by immune intolerance towards self-antigens. Some immunomodulatory probiotics have been found to regulate immune responses via tolerogenic mechanisms. Dendritic and T regulatory (Treg) cells, IL-6, IFN-γ, IL-17, and IL-23 can be considered as the most determinant dysregulated mediators in tolerogenic status. As demonstrated by documented experimental and clinical trials on inflammatory and autoimmune diseases, a number of probiotic bacterial strains can restore tolerance in host through modification of such dysregulated mediators. Since there are limited reports regarding to impact of probiotic supplementation in SLE patients, the preset review was aimed to suggest a number of probiotics bacteria, mainly from Bifidobacteria and Lactobacillus strains that are able to ameliorate immune responses. The aim was followed through literature survey on immunoregulatory probiotics that can restore tolerance and also modulate the important dysregulated pro/anti-inflammatory cytokines contributing to the pathogenesis of SLE. © 2016 Wiley Periodicals, Inc.

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes.

PubMed

Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-Sang J; Moscalu, Stefan; Jankowski, Jakub; Huang, Liping; Ye, Hong; Rosin, Diane L; Guyenet, Patrice G; Okusa, Mark D

2016-05-02

The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes.

Modulation of inflammatory bowel disease in a mouse model following infection with Trichinella spiralis

USDA-ARS?s Scientific Manuscript database

Infection of mice with Trichinella spiralis redirects the mucosal immune system from a Th1 to a protective Th2 response with a reduction in the severity of trinitrobenzesulfonic acid-induced colonic damage. T. spiralis infection induced IL-10 production in a dose-dependent manner in oxazolone (OXZ)-...

Innate immunity in renal transplantation: the role of mannose-binding lectin.

PubMed

Ibernon, Meritxell; Moreso, Francesc; Serón, Daniel

2014-01-01

Innate immune system plays an important role in the modulation of the inflammatory response during infection and tissue injury/repair. Mannose-binding lectin (MBL) is a component of the innate immune system that activates complement via the lectin pathway. Different polymorphisms of the MBL gene are associated with MBL levels and MBL function. The relationship between MBL and disease is rather complex because MBL behaves as a double-edged sword. In the general population, low serum MBL levels are associated with higher risk of infection, type 2 diabetes, autoimmune and cardiovascular disease. However, in patients with diabetes or autoimmune disease, high MBL levels are associated with more severe renal and cardiovascular comorbidities. In renal transplantation, low MBL serum levels constitute a risk factor for infection, low grade inflammation, new onset diabetes after transplantation and subclinical rejection. Despite these associations suggest that low MBL levels should be associated with poorer renal allograft outcome, epidemiological studies evaluating the predictive value of MBL levels on graft survival are controversial. Taken together, these observations suggest that low MBL serum levels modulate chronic inflammatory response that may influence transplant outcome. © 2013.

Probiotic attributes, antioxidant, anti-inflammatory and neuromodulatory effects of Enterococcus faecium CFR 3003: in vitro and in vivo evidence.

PubMed

Divyashri, G; Krishna, G; Muralidhara; Prapulla, S G

2015-12-01

Accumulating evidence suggests that probiotic bacteria play a vital role in modulating various aspects integral to the health and well-being of humans. In the present study, probiotic attributes and the antioxidant, anti-inflammatory and neuromodulatory potential of Enterococcus faecium CFR 3003 were investigated by employing suitable model systems. E. faecium exhibited robust resistance to gastrointestinal stress conditions as it could withstand acid stress at pH 1.5, 2 and 3. The bacterium also survived at a bile salt concentration of 0.45 %, and better tolerance was observed towards pepsin and trypsin. E. faecium produced lactic acid as a major metabolic product, followed by butyric acid. Lyophilized cell-free supernatant (LCS) of E. faecium exhibited significant antioxidant capacity evaluated against 1,1-diphenyl-2-picryl-hydrazyl, ascorbate auto-oxidation, oxygen radical absorbance and reducing power. Interestingly, E. faecium, Lactobacillus rhamnosus GG MTCC 1408 and LCS showed a significant anti-inflammatory effect by negatively modulating TNF-α production and upregulating IL-10 levels in LPS-stimulated macrophage cell lines. In an in vivo mice model, the propensity of probiotic supplements to modulate endogenous oxidative markers and redox status in brain regions was assessed. Young mice provided with oral supplements (daily for 28 days) of E. faecium and L. rhamnosus exhibited diminished oxidative markers in the brain and enhanced activities of antioxidant enzymes with a concomitant increase in γ-aminobutyric acid and dopamine levels. Collectively, our findings clearly suggest the propensity of these bacteria to protect against tissue damage mediated through free radicals and inflammatory cytokines. Although the underlying molecular mechanisms need further studies, it is tempting to speculate that probiotics confer a neuroprotective advantage in vivo against oxidative damage-mediated neurodegenerative conditions.

Macrophage Integrins Modulate Response to Ultra-High Molecular Weight Polyethylene Particles and Direct Particle-Induced Osteolysis

PubMed Central

Zaveri, Toral D.; Dolgova, Natalia V.; Lewis, Jamal S.; Hamaker, Kiri; Clare-Salzler, Michael J.; Keselowsky, Benjamin G.

2016-01-01

Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints. PMID:27889664

Dietary Factors in the Modulation of Inflammatory Bowel Disease Activity

PubMed Central

Shah, Shinil

2007-01-01

Context As patients look to complementary therapies for management of their diseases, it is important that the physician know the effectiveness and/or lack of effectiveness of a variety of dietary approaches/interventions. Although the pathogenesis of the inflammatory bowel diseases (ulcerative colitis and Crohn's disease) is not fully understood, many suspect that diet and various dietary factors may play a modulating role in the disease process. Evidence Acquisition The purpose of this article is to present some of what is known about various dietary/nutritional factors in inflammatory bowel disease, with inclusion of evidence from various studies regarding their putative effect. MedLINE was searched (1965-present) using combinations of the following search terms: diet, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Additionally, references of the articles obtained were searched to identify further potential sources of information. Evidence Synthesis While much information is available regarding various dietary interventions/supplements in regard to inflammatory bowel disease, the lack of controlled trials limits broad applicability. Probiotics are one of the few interventions with promising results and controlled trials. Conclusion While there are many potential and promising dietary factors that may play a role in the modulation of inflammatory bowel disease, it is prudent to await further controlled studies before broad application/physician recommendation in the noted patient population. PMID:17435660

IN VITRO LUNG ALVEOLAR EPITHELIAL CELL INJURY AND INFLAMMATORY RESPONSE TO PARTICULATE MATTER-ASSOCIATED METALS - MODULATION BY EXPOSURE TO TNF-ALPHA, IL-BETA, OR IFN-GAMMA

EPA Science Inventory

IN VITRO LUNG ALVEOLAR EPITHELIAL CELL INJURY AND INFLAMMATORY RESPONSE TO PARTICULATE MATTER-ASSOCIATED METALS - MODULATION BY EXPOSURE TO TNF , IL-1 , OR IFN .

JA Dye, KE Peoples*, CL Hayes?. US EPA, ORD, Pulmonary Toxicology Branch, RTP, NC, *HHMI-SRI, NCSU, Raleigh, NC...

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.

Immunomodulation of Parkinson's disease using Mucuna pruriens (Mp).

PubMed

Rai, Sachchida Nand; Birla, Hareram; Zahra, Walia; Singh, Saumitra Sen; Singh, Surya Pratap

2017-11-01

Immune control is associated with nigrostriatal neuroprotection for Parkinson's disease (PD); though its direct cause and effect relationships have not yet been realized and modulating the immune system for therapeutic gain has been openly discussed. While the pathobiology of PD remains in study, neuroinflammation is thought to speed nigrostriatal degeneration. The neuroinflammatory cascade associated with PD begins with aggregation of misfolded or post-translationally modified α-synuclein (α-syn). Such aggregation results in neuronal cell death and the presence of chronically activated glia (microglia and astroglia), leading to the production of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cyclooxygenase-2 (COX-2). These changes in the glial phenotype can affect the central nervous system (CNS) microenvironment by producing a pro-inflammatory milieu that speeds PD pathogenesis. Mucuna pruriens (Mp) is the most popular drug in Ayurveda, the Indian system of medicine. Several reports have suggested that it possesses analgesic, anti-inflammatory, anti-neoplastic, anti-epileptic and anti-microbial activities. Mp contain L-DOPA and ursolic acid which has an anti-inflammatory property. There are very few literatures which show the immunomodulatory activity of Mp in PD, several researchers have tried to work on the immunomodulatory activity of Mp in some other diseases. The results of several studies show that Mp modulate the immune components like TNF-α, IL-6, IFN-λ, IL-1β, iNOS and IL-2 in the CNS. It also modulates the activity of the transcription factor NF-kB which plays an important role in the progression of the PD. Thus, by altering these cytokines or transcription factors, Mp protects or prevents the progression of PD. Thus in this review we try to explore the immunomodulatory activity of Mp in PD. Copyright © 2017 Elsevier B.V. All rights reserved.

The Goldilocks Conundrum: NLR Inflammasome Modulation of Gastrointestinal Inflammation during Inflammatory Bowel Disease

PubMed Central

Ringel-Scaia, Veronica M.; McDaniel, Dylan K.; Allen, Irving C.

2017-01-01

Recent advances have revealed significant insight into Inflammatory bowel disease (IBD) pathobiology. Ulcerative colitis and Crohn's disease, the chronic relapsing clinical manifestations of IBD, are complex disorders with genetic and environmental influences. These diseases are associated with the dysregulation of immune tolerance, excessive Inflammation, and damage to the epithelial cell barrier. Increasing evidence indicates that pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs), function to maintain immune system homeostasis, modulate the gastrointestinal microbiome, and promote proper intestinal epithelial cell regeneration and repair. New insights have revealed that NLR family members are essential components in maintaining this immune system homeostasis. To date, the vast majority of studies associated with NLRs have focused on family members that form a multiprotein signaling platform called the Inflammasome. These signaling complexes are responsible for the cleavage and activation of the potent pleotropic cytokines IL-1β and IL-18, and they facilitate a unique form of cell death defined as pyroptosis. In this review, we summarize the current paradigms associated with NLR Inflammasome maintenance of immune system homeostasis in the gastrointestinal system. New concepts related to canonical and noncanonical Inflammasome signaling, as well as the implications of classical and alternative Inflammasomes in IBD pathogenesis, are also reviewed. PMID:28322135

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms.

PubMed

Alexander, Matthew R; Murgai, Meera; Moehle, Christopher W; Owens, Gary K

2012-04-02

Smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and in response to PDGF in vitro involves repression of differentiation marker genes and increases in SMC proliferation, migration, and matrix synthesis. However, SMCs within atherosclerotic plaques can also express a number of proinflammatory genes, and in cultured SMCs the inflammatory cytokine IL-1β represses SMC marker gene expression and induces inflammatory gene expression. Studies herein tested the hypothesis that IL-1β modulates SMC phenotype to a distinct inflammatory state relative to PDGF-DD. Genome-wide gene expression analysis of IL-1β- or PDGF-DD-treated SMCs revealed that although both stimuli repressed SMC differentiation marker gene expression, IL-1β distinctly induced expression of proinflammatory genes, while PDGF-DD primarily induced genes involved in cell proliferation. Promoters of inflammatory genes distinctly induced by IL-1β exhibited over-representation of NF-κB binding sites, and NF-κB inhibition in SMCs reduced IL-1β-induced upregulation of proinflammatory genes as well as repression of SMC differentiation marker genes. Interestingly, PDGF-DD-induced SMC marker gene repression was not NF-κB dependent. Finally, immunofluorescent staining of mouse atherosclerotic lesions revealed the presence of cells positive for the marker of an IL-1β-stimulated inflammatory SMC, chemokine (C-C motif) ligand 20 (CCL20), but not the PDGF-DD-induced gene, regulator of G protein signaling 17 (RGS17). Results demonstrate that IL-1β- but not PDGF-DD-induced phenotypic modulation of SMC is characterized by NF-κB-dependent activation of proinflammatory genes, suggesting the existence of a distinct inflammatory SMC phenotype. In addition, studies provide evidence for the possible utility of CCL20 and RGS17 as markers of inflammatory and proliferative state SMCs within atherosclerotic plaques in vivo.

Role of Inflammatory Signaling in the Differential Effects of Saturated and Poly-unsaturated Fatty Acids on Peripheral Circadian Clocks.

PubMed

Kim, Sam-Moon; Neuendorff, Nichole; Chapkin, Robert S; Earnest, David J

2016-05-01

Inflammatory signaling may play a role in high-fat diet (HFD)-related circadian clock disturbances that contribute to systemic metabolic dysregulation. Therefore, palmitate, the prevalent proinflammatory saturated fatty acid (SFA) in HFD and the anti-inflammatory, poly-unsaturated fatty acid (PUFA), docosahexaenoic acid (DHA), were analyzed for effects on circadian timekeeping and inflammatory responses in peripheral clocks. Prolonged palmitate, but not DHA, exposure increased the period of fibroblast Bmal1-dLuc rhythms. Acute palmitate treatment produced phase shifts of the Bmal1-dLuc rhythm that were larger in amplitude as compared to DHA. These phase-shifting effects were time-dependent and contemporaneous with rhythmic changes in palmitate-induced inflammatory responses. Fibroblast and differentiated adipocyte clocks exhibited cell-specific differences in the time-dependent nature of palmitate-induced shifts and inflammation. DHA and other inhibitors of inflammatory signaling (AICAR, cardamonin) repressed palmitate-induced proinflammatory responses and phase shifts of the fibroblast clock, suggesting that SFA-mediated inflammatory signaling may feed back to modulate circadian timekeeping in peripheral clocks. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Anti-inflammatory effect of a human prothrombin fragment-2-derived peptide, NSA9, in EOC2 microglia

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

Kim, Ji Yeon; Kim, Tae Hyong; Kim, Soung Soo

2008-04-11

Pro-inflammatory mediators, such as nitric oxide (NO), prostaglandin E{sub 2} (PGE{sub 2}), and several cytokines (tumor necrosis factor (TNF)-{alpha}, interleukin (IL)-1{beta}, and IL-6) are responsible for central nervous system (CNS) injuries that include ischemia, Alzheimer's disease, and neural death. Inhibition of these pro-inflammatory mediators would be an effective therapy to reduce the progression of neurodegenerative diseases. In this study, we examined the anti-inflammatory effects of a human prothrombin fragment-2-derived peptide, NSA9 (NSAVQLVEN), on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-activated brain microglia. NSA9 significantly inhibited the release of NO, PGE{sub 2}, and pro-inflammatory cytokines in a dose-dependent manner. Furthermore,more » NSA9 reduced the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 mRNA and protein, which control the production of NO and PGE{sub 2}, respectively. Moreover, NSA9 suppressed the LPS-induced nuclear translocation and activation of nuclear factor-{kappa}B (NF-{kappa}B). These results suggest that NSA9 strongly inhibits the pro-inflammatory responses of microglia through the modulation of NF-{kappa}B activity.« less

Bioactive dietary peptides and amino acids in inflammatory bowel disease.

PubMed

Zhang, Hua; Hu, Chien-An A; Kovacs-Nolan, Jennifer; Mine, Yoshinori

2015-10-01

Inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammation of the gastrointestinal tract. Patients affected with IBD experience symptoms including abdominal pain, persistent diarrhea, rectal bleeding, and weight loss. There is no cure for IBD; thus treatments typically focus on preventing complications, inducing and maintaining remission, and improving quality of life. During IBD, dysregulation of the intestinal immune system leads to increased production of pro-inflammatory cytokines, such as TNF-α and IL-6, and recruitment of activated immune cells to the intestine, causing tissue damage and perpetuating the inflammatory response. Recent biological therapies targeting specific inflammatory cytokines or pathways, in particular TNF-α, have shown promise, but not all patients respond to treatment, and some individuals become intolerant to treatment over time. Dietary peptides and amino acids (AAs) have been shown to modulate intestinal immune functions and influence inflammatory responses, and may be useful as alternative or ancillary treatments in IBD. This review focuses on dietary interventions for IBD treatment, in particular the role of dietary peptides and AAs in reducing inflammation, oxidative stress, and apoptosis in the gut, as well as recent advances in the cellular mechanisms responsible for their anti-inflammatory activity.

Interactions between C-reactive protein genotypes with markers of nutritional status in relation to inflammation.

PubMed

Nienaber-Rousseau, Cornelie; Swanepoel, Bianca; Dolman, Robin C; Pieters, Marlien; Conradie, Karin R; Towers, G Wayne

2014-11-11

Inflammation, as indicated by C-reactive protein concentrations (CRP), is a risk factor for chronic diseases. Both genetic and environmental factors affect susceptibility to inflammation. As dietary interventions can influence inflammatory status, we hypothesized that dietary effects could be influenced by interactions with single nucleotide polymorphisms (SNPs) in the CRP gene. We determined 12 CRP SNPs, as well as various nutrition status markers in 2010 black South Africans and analyzed their effect on CRP. Interactions were observed for several genotypes with obesity in determining CRP. Lipid intake modulated the pro-inflammatory effects of some SNPs, i.e., an increase in both saturated fatty acid and monounsaturated fatty acid intake in those homozygous for the polymorphic allele at rs2808630 was associated with a larger increase in CRP. Those harboring the minor alleles at rs3093058 and rs3093062 presented with significantly higher CRP in the presence of increased triglyceride or cholesterol intake. When harboring the minor allele of these SNPs, a high omega-6 to -3 ratio was, however, found to be anti-inflammatory. Carbohydrate intake also modulated CRP SNPs, as HbA1C and fasting glucose levels interacted with some SNPs to influence the CRP. This investigation highlights the impact that nutritional status can have on reducing the inherent genetic susceptibility to a heightened systemic inflammatory state.

Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R.

PubMed

Chakraborty, Sanjukta; Nepiyushchikh, Zhanna; Davis, Michael J; Zawieja, David C; Muthuchamy, Mariappan

2011-01-01

The aim of this study was to elucidate the molecular signaling mechanisms by which substance P (SP) modulates lymphatic muscle contraction and to determine whether SP stimulates both contractile as well as inflammatory pathways in the lymphatics. A rat mesenteric lymphatic muscle cell culture model (RMLMCs) and known specific pharmacological inhibitors were utilized to delineate SP-mediated signaling pathways in lymphatics. We detected expression of neurokinin receptor 1 (NK1R) and neurokinin receptor 3 (NK3R) in RMLMCs. SP stimulation increased phosphorylation of myosin light chain 20 (MLC₂₀) as well as p38 mitogen associated protein kinase (p38-MAPK) and extracellular signal regulated kinase (ERK1/2) indicating activation of both a contractile and a pro-inflammatory MAPK pathway. Pharmacological inhibition of both NK1R and NK3R significantly affected the downstream SP signaling. We further examined whether there was any crosstalk between the two pathways upon SP stimulation. Inhibition of ERK1/2 decreased levels of p-MLC₂₀ after SP activation, in a PKC dependent manner, indicating a potential crosstalk between these two pathways. These data provide the first evidence that SP-mediated crosstalk between pro-inflammatory and contractile signaling mechanisms exists in the lymphatic system and may be an important bridge between lymphatic function modulation and inflammation. © 2010 John Wiley & Sons Ltd.

Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R

PubMed Central

Chakraborty, Sanjukta; Nepiyushchikh, Zhanna; Davis, Michael J.; Zawieja, David C.; Muthuchamy, Mariappan

2010-01-01

Objective The aim of this study was to elucidate the molecular signaling mechanisms by which substance P (SP) modulates lymphatic muscle contraction and to determine whether SP stimulates both contractile as well as inflammatory pathways in the lymphatics. Methods A rat mesenteric lymphatic muscle cell culture model (RMLMCs) and known specific pharmacological inhibitors were utilized to delineate SP mediated signaling pathways in lymphatics. Results We detected expression of neurokinin receptor 1 (NK1R) and neurokinin receptor 3 (NK3R) in RMLMCs. SP stimulation increased phosphorylation of myosin light chain 20 (MLC20) as well as p38 mitogen associated protein kinase (p38-MAPK) and extracellular signal regulated kinase (ERK1/2) indicating activation of both a contractile and a pro-inflammatory MAPK pathway. Pharmacological inhibition of both NK1R and NK3R significantly affected the downstream SP signaling. We further examined whether there was any crosstalk between the two pathways upon SP stimulation. Inhibition of ERK1/2 decreased levels of p-MLC20 after SP activation, in a PKC dependent manner, indicating a potential crosstalk between these two pathways. Conclusions These data provide the first evidence that SP mediated crosstalk between pro-inflammatory and contractile signaling mechanisms exists in the lymphatic system and may be an important bridge between lymphatic function modulation and inflammation. PMID:21166923

Ameliorative potential of gingerol: Promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats.

PubMed

Brahma Naidu, Parim; Uddandrao, V V Sathibabu; Ravindar Naik, Ramavat; Suresh, Pothani; Meriga, Balaji; Begum, Mustapha Shabana; Pandiyan, Rajesh; Saravanan, Ganapathy

2016-01-05

Obesity, generally linked to hyperlipidemia, has been occurring of late with distressing alarm and has now become a global phenomenon casting a huge economic burden on the health care system of countries around the world. The present study investigated the effects of gingerol over 30 days on the changes in HFD-induced obese rats in marker enzymes of lipid metabolism such as fatty-acid synthase (FAS), Acetyl CoA Carboxylase (ACC), Carnitine Palmitoyl Transferase-1(CPT-1), HMG co-A Reductase (HMGR), Lecithin Choline Acyl Transferase (LCAT) and Lipoprotein Lipase (LPL) and inflammatory markers (TNF-α and IL-6). The rats were treated orally with gingerol (75 mg kg(-1)) once daily for 30 days with a lorcaserin-treated group (10 mg kg(-1)) included for comparison. Changes in body weight, glucose, insulin resistance and expressions of lipid marker enzymes and inflammatory markers in tissues were observed in experimental rats. The administration of gingerol resulted in a significant reduction in body weight gain, glucose and insulin levels, and insulin resistance, which altered the activity, expressions of lipid marker enzymes and inflammatory markers. It showed that gingerol had significantly altered these parameters when compared with HFD control rats. This study confirms that gingerol prevents HFD-induced hyperlipidemia by modulating the expression of enzymes important to cholesterol metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

PubMed

Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Helminths in the gastrointestinal tract as modulators of immunity and pathology

PubMed Central

Varyani, Fumi; Fleming, John O.

2017-01-01

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract. PMID:28302598

Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years.

PubMed

Federico, Alessandro; Dallio, Marcello; Loguercio, Carmelina

2017-01-24

Silymarin is the extract of Silybum marianum , or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.

Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients

PubMed Central

Dispenza, Melanie C.; Wolpert, Ellen B.; Gilliland, Kathryn L.; Dai, Pingqi; Cong, Zhaoyuan; Nelson, Amanda M.; Thiboutot, Diane M.

2012-01-01

Retinoids are used in the treatment of inflammatory skin diseases and malignancies, but studies characterizing the in vivo actions of these drugs in humans are lacking. Isotretinoin is a pro-drug for all-trans retinoic acid that can induce long-term remissions of acne; however, its complete mechanism of action is unknown. We hypothesized that isotretinoin induces remission of acne by normalizing the innate immune response to the commensal bacterium P. acnes. Compared to normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of TLR-2 and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes by one week of therapy. This effect was sustained six months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects in acne. The modulation of TLR-2 expression on monocytes has important implications in other inflammatory disorders characterized by TLR-2 dysregulation. PMID:22513780

Vagus-brain communication in atherosclerosis-related inflammation: a neuroimmunomodulation perspective of CAD.

PubMed

Gidron, Yori; Kupper, Nina; Kwaijtaal, Martijn; Winter, Jobst; Denollet, Johan

2007-12-01

The current understanding of the pathophysiology of atherosclerosis leading to coronary artery disease (CAD) emphasizes the role of inflammatory mediators. Given the bidirectional communication between the immune and central nervous systems, an important question is whether the brain can be "informed" about and modulate CAD-related inflammation. A candidate communicator and modulator is the vagus nerve. Until now, the vagus nerve has received attention in cardiology mainly due to its role in the parasympathetic cardiovascular response. However, the vagus nerve can also "inform" the brain about peripheral inflammation since its paraganglia have receptors for interleukin-1. Furthermore, its efferent branch has a local anti-inflammatory effect. These effects have not been considered in research on the vagus nerve in CAD or in vagus nerve stimulation trials in CAD. In addition, various behavioural interventions, including relaxation, may influence CAD prognosis by affecting vagal activity. Based on this converging evidence, we propose a neuroimmunomodulation approach to atherogenesis. In this model, the vagus nerve "informs" the brain about CAD-related cytokines; in turn, activation of the vagus (via vagus nerve stimulation, vagomimetic drugs or relaxation) induces an anti-inflammatory response that can slow down the chronic process of atherogenesis.

Obesity-induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

PubMed Central

Fuster, Jose J.; Ouchi, Noriyuki; Gokce, Noyan; Walsh, Kenneth

2016-01-01

Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the “collateral damage” of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of pro-inflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines. PMID:27230642

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance.

PubMed

Newton, Robert; Shah, Suharsh; Altonsy, Mohammed O; Gerber, Antony N

2017-04-28

Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review.

PubMed

Zhu, Fengmei; Du, Bin; Xu, Baojun

2018-05-24

Inflammation is the first biological response of the immune system to infection, injury or irritation. Evidence suggests that the anti-inflammatory effect is mediated through the regulation of various inflammatory cytokines, such as nitric oxide, interleukins, tumor necrosis factor alpha-α, interferon gamma-γ as well as noncytokine mediator, prostaglandin E 2 . Fruits, vegetables, and food legumes contain high levels of phytochemicals that show anti-inflammatory effect, but their mechanisms of actions have not been completely identified. The aim of this paper was to summarize the recent investigations and findings regarding in vitro and animal model studies on the anti-inflammatory effects of fruits, vegetables, and food legumes. Specific cytokines released for specific type of physiological event might shed some light on the specific use of each source of phytochemicals that can benefit to counter the inflammatory response. As natural modulators of proinflammatory gene expressions, phytochemical from fruits, vegetables, and food legumes could be incorporated into novel bioactive anti-inflammatory formulations of various nutraceuticals and pharmaceuticals. Finally, these phytochemicals are discussed as the natural promotion strategy for the improvement of human health status. The phenolics and triterpenoids in fruits and vegetables showed higher anti-inflammatory activity than other compounds. In food legumes, lectins and peptides had anti-inflammatory activity in most cases. However, there are lack of human study data on the anti-inflammatory activity of phytochemicals from fruits, vegetables, and food legumes.

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

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system.

PubMed

St Pierre, Cristina; Guo, Jane; Shin, John D; Engstrom, Laura W; Lee, Hyun-Hee; Herbert, Alan; Surdi, Laura; Baker, James; Salmon, Michael; Shah, Sanjiv; Ellis, J Michael; Houshyar, Hani; Crackower, Michael A; Kleinschek, Melanie A; Jones, Dallas C; Hicks, Alexandra; Zaller, Dennis M; Alves, Stephen E; Ramadas, Ravisankar A

2017-01-01

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

Diplomatic Assistance: Can Helminth-Modulated Macrophages Act as Treatment for Inflammatory Disease?

PubMed Central

Steinfelder, Svenja; O’Regan, Noëlle Louise; Hartmann, Susanne

2016-01-01

Helminths have evolved numerous pathways to prevent their expulsion or elimination from the host to ensure long-term survival. During infection, they target numerous host cells, including macrophages, to induce an alternatively activated phenotype, which aids elimination of infection, tissue repair, and wound healing. Multiple animal-based studies have demonstrated a significant reduction or complete reversal of disease by helminth infection, treatment with helminth products, or helminth-modulated macrophages in models of allergy, autoimmunity, and sepsis. Experimental studies of macrophage and helminth therapies are being translated into clinical benefits for patients undergoing transplantation and those with multiple sclerosis. Thus, helminths or helminth-modulated macrophages present great possibilities as therapeutic applications for inflammatory diseases in humans. Macrophage-based helminth therapies and the underlying mechanisms of their therapeutic or curative effects represent an under-researched area with the potential to open new avenues of treatment. This review explores the application of helminth-modulated macrophages as a new therapy for inflammatory diseases. PMID:27101372

NK cells modulate the inflammatory response to corneal epithelial abrasion and thereby support wound healing

USDA-ARS?s Scientific Manuscript database

Natural killer cells are lymphocytes of the innate immune system that have crucial cytotoxic and regulatory roles in adaptive immunity and inflammation. Herein, we consider a role for these cells in corneal wound healing. After a 2-mm central epithelial abrasion of the mouse cornea, a subset of clas...

[Phosphorylation of protein kinase C in cerebrospinal fluid-contacting nucleus modulates the inflammatory pain in rats].

PubMed

Zhou, Fang; Wang, Jia-You; Tian, En-Qi; Zhang, Li-Cai

2015-12-25

The present study was aimed to investigate the role of cerebrospinal fluid-contacting nucleus (CSF-CN) neurons in modulation of inflammatory pain and underlying mechanism. The inflammatory pain model was made by subcutaneous injection of the complete Freund's adjuvant (CFA) into the left hind paw of rats. The phosphorylation level of PKC (p-PKC) was examined by Western blot. Thermal withdrawal latency (TWL) of the rats was measured to assess inflammatory pain. The results showed that, compared with the sham controls, the inflammatory pain model rats showed shortened TWL on day 1, 3, and 7 after CFA injection, as well as increased level of p-PKC in CSF-CN neurons at 24 h after CFA injection. The administration of GF109203X, a PKC inhibitor, into lateral ventricle decreased the level of p-PKC protein expression and increased TWL in the model rats. These results suggest that blocking the PKC pathway in CSF-CN neurons may be an effective way to reduce or eliminate the inflammatory pain.

Clinical implications of basic science discoveries: nociceptive neurons as targets to control immunity--potential relevance for transplantation.

PubMed

Larregina, A T; Divito, S J; Morelli, A E

2015-06-01

Increasing evidence indicates the existence of a complex cross-regulation between the most important biosensors of the human body: The immune and nervous systems. Cytokines control body temperature and trigger autoimmune disorders in the central nervous system, whereas neuropeptides released in peripheral tissues and lymphoid organs modulate inflammatory (innate) and adaptive immune responses. Surprisingly, the effects of nerve fibers and the antidromic release of its pro-inflammatory neuropeptides on the leukocytes of the immune system that mediate graft rejection are practically unknown. In the transplantation field, such area of research remains practically unexplored. A recent study by Riol-Blanco et al has revealed new details on how nociceptive nerves regulate the pro-inflammatory function of leukocytes in peripheral tissues. Although the mechanism(s) by which neuroinflammation affects the immune response against the allograft remains unknown, recent data suggest that this new area of research is worth exploring for potential development of novel complementary therapies for prevention/treatment of graft rejection. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.

PubMed

Maes, Michael; Nowak, Gabriel; Caso, Javier R; Leza, Juan Carlos; Song, Cai; Kubera, Marta; Klein, Hans; Galecki, Piotr; Noto, Cristiano; Glaab, Enrico; Balling, Rudi; Berk, Michael

2016-07-01

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on inflammatory and neuropathic pain in mice.

PubMed

Marabese, I; de Novellis, V; Palazzo, E; Scafuro, M A; Vita, D; Rossi, F; Maione, S

2007-02-01

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Adrenal-Derived Hormones Differentially Modulate Intestinal Immunity in Experimental Colitis

PubMed Central

de Souza, Patrícia Reis; Basso, Paulo José; Nardini, Viviani; Silva, Angelica; Banquieri, Fernanda

2016-01-01

The adrenal glands are able to modulate immune responses through neuroimmunoendocrine interactions and cortisol secretion that could suppress exacerbated inflammation such as in inflammatory bowel disease (IBD). Therefore, here we evaluated the role of these glands in experimental colitis induced by 3% dextran sulfate sodium (DSS) in C57BL/6 mice subjected to adrenalectomy, with or without glucocorticoid (GC) replacement. Mice succumbed to colitis without adrenals with a higher clinical score and augmented systemic levels of IL-6 and lower LPS. Furthermore, adrenalectomy negatively modulated systemic regulatory markers. The absence of adrenals resulted in augmented tolerogenic lamina propria dendritic cells but no compensatory local production of corticosterone and decreased mucosal inflammation associated with increased IFN-γ and FasL in the intestine. To clarify the importance of GC in this scenario, GC replacement in adrenalectomized mice restored different markers to the same degree of that observed in DSS group. Finally, this is the first time that adrenal-derived hormones, especially GC, were associated with the differential local modulation of the gut infiltrate, also pointing to a relationship between adrenalectomy and the modulation of systemic regulatory markers. These findings may elucidate some neuroimmunoendocrine mechanisms that dictate colitis outcome. PMID:27403034

Nanoparticle distribution during systemic inflammation is size-dependent and organ-specific

NASA Astrophysics Data System (ADS)

Chen, K.-H.; Lundy, D. J.; Toh, E. K.-W.; Chen, C.-H.; Shih, C.; Chen, P.; Chang, H.-C.; Lai, J. J.; Stayton, P. S.; Hoffman, A. S.; Hsieh, P. C.-H.

2015-09-01

This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner.This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner. Electronic supplementary information (ESI) available: IF images of brain, heart, low magnification images of spleen, mouse heart rate and blood pressure post-LPS. See DOI: 10.1039/c5nr03626g

Curcumin Modulates the Inflammatory Response and Inhibits Subsequent Fibrosis in a Mouse Model of Viral-induced Acute Respiratory Distress Syndrome

PubMed Central

Liu, Guangliang; Wang, Ruixue; London, Steven D.; London, Lucille

2013-01-01

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 107 pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation. PMID:23437361

Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome.

PubMed

Avasarala, Sreedevi; Zhang, Fangfang; Liu, Guangliang; Wang, Ruixue; London, Steven D; London, Lucille

2013-01-01

Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10(7)pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation.

Experimental Evidence of ω-3 Polyunsaturated Fatty Acid Modulation of Inflammatory Cytokines and Bioactive Lipid Mediators: Their Potential Role in Inflammatory, Neurodegenerative, and Neoplastic Diseases

PubMed Central

Calviello, Gabriella; Su, Hui-Min; Weylandt, Karsten H.; Fasano, Elena; Serini, Simona; Cittadini, Achille

2013-01-01

A large body of evidence has emerged over the past years to show the critical role played by inflammation in the pathogenesis of several diseases including some cardiovascular, neoplastic, and neurodegenerative diseases, previously not considered inflammation-related. The anti-inflammatory action of ω-3 polyunsaturated fatty acids (PUFAs), as well as their potential healthy effects against the development and progression of the same diseases, has been widely studied by our and others' laboratories. As a result, a rethinking is taking place on the possible mechanisms underlying the beneficial effects of ω-3 PUFAs against these disorders, and, in particular, on the influence that they may exert on the molecular pathways involved in inflammatory process, including the production of inflammatory cytokines and lipid mediators active in the resolving phase of inflammation. In the present review we will summarize and discuss the current knowledge regarding the modulating effects of ω-3 PUFAs on the production of inflammatory cytokines and proresolving or protective lipid mediators in the context of inflammatory, metabolic, neurodegenerative, and neoplastic diseases. PMID:23691510

The Role of Chalcones in Suppression of NF-κB-Mediated Inflammation and Cancer

PubMed Central

Yadav, Vivek R.; Prasad, Sahdeo; Sung, Bokyung; Aggarwal, Bharat B.

2010-01-01

Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2′,4′-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review. PMID:21184860

α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way.

PubMed

Grandi, Andrea; Zini, Irene; Flammini, Lisa; Cantoni, Anna M; Vivo, Valentina; Ballabeni, Vigilio; Barocelli, Elisabetta; Bertoni, Simona

2017-01-01

The existence of a cholinergic anti-inflammatory pathway negatively modulating the inflammatory and immune responses in various clinical conditions and experimental models has long been postulated. In particular, the protective involvement of the vagus nerve and of nicotinic Ach receptors (nAChRs) has been proposed in intestinal inflammation and repeatedly investigated in DSS- and TNBS-induced colitis. However, the role of α 7 nAChRs stimulation is still controversial and the potential contribution of α 4 β 2 nAChRs has never been explored in this experimental condition. Our aims were therefore to pharmacologically investigate the role played by both α 7 and α 4 β 2 nAChRs in the modulation of the local and systemic inflammatory responses activated in TNBS-induced colitis in mice and to assess the involvement of the spleen in nicotinic responses. To this end, TNBS-exposed mice were sub-acutely treated with various subcutaneous doses of highly selective agonists (AR-R17779 and TC-2403) and antagonists (methyllycaconitine and dihydro-β-erythroidine) of α 7 and α 4 β 2 nAChRs, respectively, or with sulfasalazine 50 mg/kg per os and clinical and inflammatory responses were evaluated by means of biochemical, histological and flow cytometry assays. α 4 β 2 ligands evoked weak and contradictory effects, while α 7 nAChR agonist AR-R17779 emerged as the most beneficial treatment, able to attenuate several local markers of colitis severity and to revert the rise in splenic T-cells and in colonic inflammatory cytokines levels induced by haptenization. After splenectomy, AR-R17779 lost its protective effects, demonstrating for the first time that, in TNBS-model of experimental colitis, the anti-inflammatory effect of exogenous α 7 nAChR stimulation is strictly spleen-dependent. Our findings showed that the selective α 7 nAChRs agonist AR-R17779 exerted beneficial effects in a model of intestinal inflammation characterized by activation of the adaptive immune system and that the spleen is essential to mediate this cholinergic protection.

Flavonoid Naringenin: A Potential Immunomodulator for Chlamydia trachomatis Inflammation

PubMed Central

Yilma, Abebayehu N.; Singh, Shree R.; Morici, Lisa; Dennis, Vida A.

2013-01-01

Chlamydia trachomatis, the agent of bacterial sexually transmitted infections, can manifest itself as either acute cervicitis, pelvic inflammatory disease, or a chronic asymptomatic infection. Inflammation induced by C. trachomatis contributes greatly to the pathogenesis of disease. Here we evaluated the anti-inflammatory capacity of naringenin, a polyphenolic compound, to modulate inflammatory mediators produced by mouse J774 macrophages infected with live C. trachomatis. Infected macrophages produced a broad spectrum of inflammatory cytokines (GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10) and chemokines (CCL4, CCL5, CXCL1, CXCL5, and CXCL10) which were downregulated by naringenin in a dose-dependent manner. Enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4 in addition to the CD86 costimulatory molecule on infected macrophages were modulated by naringenin. Pathway-specific inhibition studies disclosed that p38 mitogen-activated-protein kinase (MAPK) is involved in the production of inflammatory mediators by infected macrophages. Notably, naringenin inhibited the ability of C. trachomatis to phosphorylate p38 in macrophages, suggesting a potential mechanism of its attenuation of concomitantly produced inflammatory mediators. Our data demonstrates that naringenin is an immunomodulator of inflammation triggered by C. trachomatis, which possibly may be mediated upstream by modulation of TLR2, TLR4, and CD86 receptors on infected macrophages and downstream via the p38 MAPK pathway. PMID:23766556

A long noncoding RNA, lincRNA-Tnfaip3, acts as a coregulator of NF-κB to modulate inflammatory gene transcription in mouse macrophages.

PubMed

Ma, Shibin; Ming, Zhenping; Gong, Ai-Yu; Wang, Yang; Chen, Xiqiang; Hu, Guoku; Zhou, Rui; Shibata, Annemarie; Swanson, Patrick C; Chen, Xian-Ming

2017-03-01

Long intergenic noncoding RNAs (lincRNAs) are long noncoding transcripts (>200 nt) from the intergenic regions of annotated protein-coding genes. We report here that the lincRNA gene lincRNA-Tnfaip3 , located at mouse chromosome 10 proximal to the tumor necrosis factor α-induced protein 3 ( Tnfaip3 ) gene, is an early-primary response gene controlled by nuclear factor-κB (NF-κB) signaling in murine macrophages. Functionally, lincRNA- Tnfaip3 appears to mediate both the activation and repression of distinct classes of inflammatory genes in macrophages. Specifically, induction of lincRNA-Tnfaip3 is required for the transactivation of NF-κB-regulated inflammatory genes in response to bacterial LPSs stimulation. LincRNA-Tnfaip3 physically interacts with the high-mobility group box 1 (Hmgb1), assembling a NF-κB/Hmgb1/lincRNA-Tnfaip3 complex in macrophages after LPS stimulation. This resultant NF-κB/Hmgb1/lincRNA-Tnfaip3 complex can modulate Hmgb1-associated histone modifications and, ultimately, transactivation of inflammatory genes in mouse macrophages in response to microbial challenge. Therefore, our data indicate a new regulatory role of NF-κB-induced lincRNA-Tnfaip3 to act as a coactivator of NF-κB for the transcription of inflammatory genes in innate immune cells through modulation of epigenetic chromatin remodeling.-Ma, S., Ming, Z., Gong, A.-Y., Wang, Y., Chen, X., Hu, G., Zhou, R., Shibata, A., Swanson, P. C., Chen, X.-M. A long noncoding RNA, LincRNA-Tnfaip3, acts as a coregulator of NF-κB to modulate inflammatory gene transcription in mouse macrophages. © FASEB.

Walnut extract modulates activation of microglia through alteration in intracellular calcium concentration

USDA-ARS?s Scientific Manuscript database

Previous data from our laboratory demonstrated that treatment with walnut extracts (WN) protects cells against oxidative and inflammatory cytotoxicity and promotes anti-inflammatory activities. The current study was undertaken to test whether the anti-inflammatory effects of WN are attributed to its...

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge.

PubMed

Surkin, P N; Di Rosso, M E; Correa, F; Elverdin, J C; Genaro, A M; De Laurentiis, A; Fernández-Solari, J

2017-08-01

Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 μL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration. © 2017 British Society for Neuroendocrinology.

Vesicular acetylcholine transporter knock down-mice are more susceptible to inflammation, c-Fos expression and sickness behavior induced by lipopolysaccharide.

PubMed

Leite, Hércules Ribeiro; Oliveira-Lima, Onésia Cristina de; Pereira, Luciana de Melo; Oliveira, Vinícius Elias de Moura; Prado, Vania Ferreira; Prado, Marco Antônio Máximo; Pereira, Grace Schenatto; Massensini, André Ricardo

2016-10-01

In addition to the well-known functions as a neurotransmitter, acetylcholine (ACh) can modulate of the immune system. Nonetheless, how endogenous ACh release inflammatory responses is still not clear. To address this question, we took advantage of an animal model with a decreased ACh release due a reduction (knockdown) in vesicular acetylcholine transporter (VAChT) expression (VAChT-KD(HOM)). These animals were challenged with lipopolysaccharide (LPS). Afterwards, we evaluated sickness behavior and quantified systemic and cerebral inflammation as well as neuronal activation in the dorsal vagal complex (DVC). VAChT-KD(HOM) mice that were injected with LPS (10mg/kg) showed increased mortality rate as compared to control mice. In line with this result, a low dose of LPS (0.1mg/kg) increased the levels of pro-inflammatory (TNF-α, IL-1β, and IL-6) and anti-inflammatory (IL-10) cytokines in the spleen and brain of VAChT-KD(HOM) mice in comparison with controls. Similarly, serum levels of TNF-α and IL-6 were increased in VAChT-KD(HOM) mice. This excessive cytokine production was completely prevented by administration of a nicotinic receptor agonist (0.4mg/kg) prior to the LPS injection. Three hours after the LPS injection, c-Fos expression increased in the DVC region of VAChT-KD(HOM) mice compared to controls. In addition, VAChT-KD(HOM) mice showed behavioral changes such as lowered locomotor and exploratory activity and reduced social interaction after the LPS challenge, when compared to control mice. Taken together, our results show that the decreased ability to release ACh exacerbates systemic and cerebral inflammation and promotes neural activation and behavioral changes induced by LPS. In conclusion, our findings support the notion that activity of cholinergic pathways, which can be modulated by VAChT expression, controls inflammatory and neural responses to LPS challenge. Copyright © 2016 Elsevier Inc. All rights reserved.

Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate

PubMed Central

Gallo, Antonella; Passaro, Giovanna; Gasbarrini, Antonio; Landolfi, Raffaele; Montalto, Massimo

2016-01-01

Alterations of intestinal microflora may significantly contribute to the pathogenesis of different inflammatory and autoimmune disorders. There is emerging interest on the role of selective modulation of microflora in inducing benefits in inflammatory intestinal disorders, by as probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). To summarize recent evidences on microflora modulation in main intestinal inflammatory disorders, PubMed was searched using terms microbiota, intestinal flora, probiotics, prebiotics, fecal transplantation. More than three hundred articles published up to 2015 were selected and reviewed. Randomized placebo-controlled trials and meta-analysis were firstly included, mainly for probiotics. A meta-analysis was not performed because of the heterogeneity of these studies. Most of relevant data derived from studies on probiotics, reporting some efficacy in ulcerative colitis and in pouchitis, while disappointing results are available for Crohn’s disease. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea. Efficacy of probiotics in NSAID enteropathy and irritable bowel syndrome is still controversial. Finally, FMT has been recently recognized as an efficacious treatment for recurrent Clostridium difficile infection. Modulation of intestinal flora represents a very interesting therapeutic target, although it still deserves some doubts and limitations. Future studies should be encouraged to provide new understanding about its therapeutical role. PMID:27621567

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes

PubMed Central

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2018-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed—Schistosoma infection and Schistosoma-derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma-derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D. PMID:29387059

Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes.

PubMed

Tang, Chun-Lian; Liu, Zhi-Ming; Gao, Yan Ru; Xiong, Fei

2017-01-01

Studies on parasite-induced immunoregulatory mechanisms could contribute to the development of new therapies for inflammatory diseases such as type 2 diabetes (T2D), which is a chronic inflammatory disease characterized by persistent elevated glucose levels due to insulin resistance. The association between previous Schistosoma infection and T2D has been confirmed- Schistosoma infection and Schistosoma -derived products modulate the immune system, including innate and acquired immune responses, contributing to T2D disease control. Schistosoma infections and Schistosoma -derived molecules affect the immune cell composition in adipose tissue, dampening inflammation and improving glucose tolerance. This protective role includes the polarization of immune cells to alternatively activated macrophages, dendritic cells, eosinophils, and group 2 innate lymphoid cells. Furthermore, Schistosoma infection and Schistosoma products are effective for the treatment of T2D, as they increase the number of type 2 helper T cells (Th2) and regulatory T cells (Tregs) and decrease type 1 helper T cells (Th1) and type 17 helper T cells (Th17) cells. Thus, our aim was to comprehensively review the mechanism through which Schistosoma infection and Schistosoma products modulate the immune response against T2D.

Plasma inflammatory biomarkers response to aerobic versus resisted exercise training for chronic obstructive pulmonary disease patients.

PubMed

Abd El-Kader, Shehab M; Al-Jiffri, Osama H; Al-Shreef, Fadwa M

2016-06-01

Chronic obstructive pulmonary disease (COPD) is a main risk for morbidity, associated with alterations in systemic inflammation. Recent studies proved that morbidity and mortality of COPD is related to systemic inflammation as it contributes to the pathogenesis of atherosclerosis and cardiovascular disease. However, increase of inflammatory cytokines adversely affects quality of life, alteration in ventilatory and skeletal muscles functions. Moreover, exercise training has many beneficial effects in correction of the adverse effects of COPD. This study aimed to compare the response of inflammatory cytokines of COPD to aerobic versus resisted exercises. One hundred COPD diseased patients participated in this study and were randomly included in two groups; the first group received aerobic exercise, whereas the second group received resisted exercise training for 12 weeks. The mean values of TNF-α, Il-2, IL-4, IL-6 and CRP were significantly decreased in both groups. Also; there was a significant difference between both groups at the end of the study with more reduction in patients who received aerobic exercise training. Aerobic exercise is more appropriate than resisted exercise training in modulating inflammatory cytokines level in patients with chronic obstructive pulmonary disease.

Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease

PubMed Central

Steven, Sebastian; Münzel, Thomas; Daiber, Andreas

2015-01-01

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease. PMID:26251902

Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

PubMed Central

Kim, Yong Sook; Jeong, Hye-yun; Kim, Ah Ra; Kim, Woong-Hee; Cho, Haaglim; Um, JungIn; Seo, Youngha; Kang, Wan Seok; Jin, Suk-Won; Kim, Min Chul; Kim, Yong-Chul; Jung, Da-Woon; Williams, Darren R.; Ahn, Youngkeun

2016-01-01

The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2′Z,3′E)-6-Bromoindirubin-3′-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID:27510556

Helminths in the gastrointestinal tract as modulators of immunity and pathology.

PubMed

Varyani, Fumi; Fleming, John O; Maizels, Rick M

2017-06-01

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract. Copyright © 2017 the American Physiological Society.

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.

Tuning constitutive and pathological inflammation in the gut via the interaction of dietary nitrate and polyphenols with host microbiome.

PubMed

Rocha, Bárbara S; Nunes, Carla; Laranjinha, João

2016-12-01

Chronic inflammation is currently recognized as a critical process in modern-era epidemics such as diabetes, obesity and neurodegeneration. However, little attention is paid to the constitutive inflammatory pathways that operate in the gut and that are mandatory for local welfare and the prevention of such multi-organic diseases. Hence, the digestive system, while posing as a barrier between the external environment and the host, is crucial for the balance between constitutive and pathological inflammatory events. Gut microbiome, a recently discovered organ, is now known to govern the interaction between exogenous agents and the host with ensued impact on local and systemic homeostasis. Whereas gut microbiota may be modulated by a myriad of factors, diet constitutes one of its major determinants. Thus, dietary compounds that influence microbial flora may thereby impact on inflammatory pathways. One such example is the redox environment in the gut lumen which is highly dependent on the local generation of nitric oxide along the nitrate-nitrite-nitric oxide pathway and that is further enhanced by simultaneous consumption of polyphenols. In this paper, different pathways encompassing the interaction of dietary nitrate and polyphenols with gut microbiota will be presented and discussed in connection with local and systemic inflammatory events. Furthermore, it will be discussed how these interactive cycles (nitrate-polyphenols-microbiome) may pose as novel strategies to tackle inflammatory diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Local and Systemic Inflammatory Biomarkers of Diabetic Retinopathy: An Integrative Approach.

PubMed

Vujosevic, Stela; Simó, Rafael

2017-05-01

To review the usefulness of local and systemic inflammatory biomarkers of diabetic retinopathy (DR) to implement a more personalized treatment. An integrated research (from ophthalmologist and diabetologist point of view) of most significant literature on serum, vitreous, and aqueous humor (AH) biochemical biomarkers related to inflammation at early and advanced stages of DR (including diabetic macular edema [DME] and proliferative DR) was performed. Moreover, novel imaging retinal biomarkers of local "inflammatory condition" were described. Multiple inflammatory cytokines and chemokines are increased in DR in both serum as well as in the eye (vitreous and AH). Nevertheless, local rather than systemic production of proinflammatory cytokines seems more relevant in the pathogenesis of both DR and DME. In the eye, retinal glia cells (macroglia and microglia) together with RPE are major sources of proinflammatory and angiogenic modulators. Retinal imaging allows for noninvasive clinical evaluation of retinal inflammatory response induced by diabetes mellitus. Proinflammatory cytokines/chemokines play an essential role in the pathogenesis of DR. Therefore, circulating biomarkers and retinal imaging aimed at assessing inflammation have emerged as useful tools for monitoring the onset and progression of DR. In addition, "liquid biopsy" of AH seems a good option in patients with advanced stages of DR requiring intravitreous injections. This strategy may permit us to implement a more personalized treatment with better visual function outcome. Further evaluation and validation of circulating and local biomarkers, as well as multimodal imaging is needed to gain new insights into this issue.

Cocoa Polyphenols and Inflammatory Markers of Cardiovascular Disease

PubMed Central

Khan, Nasiruddin; Khymenets, Olha; Urpí-Sardà, Mireia; Tulipani, Sara; Garcia-Aloy, Mar; Monagas, María; Mora-Cubillos, Ximena; Llorach, Rafael; Andres-Lacueva, Cristina

2014-01-01

Epidemiological studies have demonstrated the beneficial effect of plant-derived food intake in reducing the risk of cardiovascular disease (CVD). The potential bioactivity of cocoa and its polyphenolic components in modulating cardiovascular health is now being studied worldwide and continues to grow at a rapid pace. In fact, the high polyphenol content of cocoa is of particular interest from the nutritional and pharmacological viewpoints. Cocoa polyphenols are shown to possess a range of cardiovascular-protective properties, and can play a meaningful role through modulating different inflammatory markers involved in atherosclerosis. Accumulated evidence on related anti-inflammatory effects of cocoa polyphenols is summarized in the present review. PMID:24566441

Inhibition of pro-inflammatory mediators: role of Bacopa monniera (L.) Wettst.

PubMed

Viji, Vijayan; Helen, Antony

2011-10-01

Bacopa monniera (L.) Wettst is a renowned plant in the Ayurvedic system of medicine. The present study seeks to identify the anti-inflammatory activity of two fractions from the methanolic extract of Bacopa, viz. the triterpenoid and bacoside-enriched fractions. The ability of these two fractions to inhibit the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 was tested using lipopolysaccharide (LPS)-activated peripheral blood mononuclear cells and peritoneal exudate cells in vitro. We found that triterpenoid and bacoside-enriched fractions significantly inhibited LPS-activated TNF-α, IL-6 and nitrite production in mononuclear cells. Significant antioxidant activity was exhibited by the bacoside enriched fraction compared to the triterpenoid fraction. Carrageenan-induced hind paw oedema assay revealed that triterpenoid and bacoside-enriched fractions exerted anti-oedematogenic effect, while in the arthritis model only the triterpenoid fraction exerted an anti-arthritic potential. The present study provides an insight into the ability of Bacopa monniera to inhibit inflammation through modulation of pro-inflammatory mediator release.

Neuro-Modulation of Immuno-Endocrine Response Induced by Kaliotoxin of Androctonus Scorpion Venom.

PubMed

Ladjel-Mendil, Amina; Martin-Eauclaire, Marie-France; Laraba-Djebari, Fatima

2016-12-01

Kaliotoxin (KTX), a specific blocker of potassium channels, exerts various toxic effects due to its action on the central nervous system. Its use in experimental model could help the understanding of the cellular and molecular mechanisms involved in the neuropathological processes related to potassium channel dysfunctions. In this study, the ability of KTX to stimulate neuro-immuno-endocrine axis was investigated. As results, the intracerebroventricular injection of KTX leads to severe structural-functional alterations of both hypothalamus and thyroid. These alterations were characterized by a massive release of hormones' markers of thyroid function associated with damaged tissue which was infiltrated by inflammatory cell and an imbalanced redox status. Taken together, these data highlight that KTX is able to modulate the neuro-endocrine response after binding to its targets leading to the hypothalamus and the thyroid stimulation, probably by inflammatory response activation and the installation of oxidative stress in these organs. © 2016 Wiley Periodicals, Inc.

Lysophosphatidylcholine: A Novel Modulator of Trypanosoma cruzi Transmission

PubMed Central

Silva-Neto, Mário A. C.; Carneiro, Alan B.; Silva-Cardoso, Livia; Atella, Georgia C.

2012-01-01

Lysophosphatidylcholine is a bioactive lipid that regulates a large number of cellular processes and is especially present during the deposition and infiltration of inflammatory cells and deposition of atheromatous plaque. Such molecule is also present in saliva and feces of the hematophagous organism Rhodnius prolixus, a triatominae bug vector of Chagas disease. We have recently demonstrated that LPC is a modulator of Trypanosoma cruzi transmission. It acts as a powerful chemoattractant for inflammatory cells at the site of the insect bite, which will provide a concentrated population of cells available for parasite infection. Also, LPC increases macrophage intracellular calcium concentrations that ultimately enhance parasite invasion. Finally, LPC inhibits NO production by macrophages stimulated by live T. cruzi, and thus interferes with the immune system of the vertebrate host. In the present paper, we discuss the main signaling mechanisms that are likely used by such molecule and their eventual use as targets to block parasite transmission and the pathogenesis of Chagas disease. PMID:22132309

Estrogen receptor alpha modulates toll-like receptor signaling in murine lupus

PubMed Central

Cunningham, Melissa A.; Naga, Osama S.; Eudaly, Jackie G.; Scott, Jennifer L.; Gilkeson, Gary S.

2013-01-01

Systemic lupus erythematosus (SLE) is a disease that disproportionately affects females. Despite significant research effort, the mechanisms underlying the female predominance in this disease are largely unknown. Previously, we showed that estrogen receptor alpha knockout (ERαKO) lupus prone female mice had significantly less pathologic renal disease and proteinuria, and significantly prolonged survival. Since autoantibody levels and number and percentage of B/T cells were not significantly impacted by ERα genotype, we hypothesized that the primary benefit of ERα deficiency in lupus nephritis was via modulation of the innate immune response. Using BMDCs and spleen cells/B cells from female wild-type or ERαKO mice, we found that ERαKO-derived cells have a significantly reduced inflammatory response after stimulation with TLR agonists. Our results indicate that the inflammatory response to TLR ligands is significantly impacted by the presence of ERα despite the absence of estradiol, and may partially explain the protective effect of ERα deficiency in lupus-prone animals. PMID:22659029

Diagnosis of inflammatory rheumatic diseases with photon density waves

NASA Astrophysics Data System (ADS)

Beuthan, Juergen; Prapavat, Viravuth; Naber, Rolf-Dieter; Minet, Olaf; Mueller, Gerhard J.

1996-04-01

Rheumatoid arthritis (RA) is a common inflammatory disease of interphalangeal joints. The utilization of conventional imaging systems (e.g. x-rays) for non invasive diagnostics at an early stage of the disease is difficult, since pathologically induced changes do not occur at this stage in hard tissue. Use of MR and ultrasound methods are both methodically problematic and expensive. Therefore investigations for optical diagnostics using photon density waves (PDW) were carried out. The PDW was realized with an intensity modulated laser diode (825 nm, fmod: 110 MHz) and an ac- and phase detection in a 2D transillumination scanner. Measurements of optical properties of synovia and synovialis of healthy and early RA stages were performed and indicated a significant pathological increase of (mu) s. The detected PDW-pictures provided corresponding results. Further investigations regarding the object- variation of the modulation transfer function provide a sufficient spatial resolution in order to assign functional changes to anatomical structures. The results are presented using photos.

5-AED Enhances Survival of Irradiated Mice in a G-CSF-Dependent Manner, Stimulates Innate Immune Cell Function, Reduces Radiation-Induced DNA Damage and Induces Genes that Modulate Cell Cycle Progression and Apoptosis

DTIC Science & Technology

2012-07-22

modulate cell cycle progression and apoptosis. INTRODUCTION Because of the increasing threat posed by nuclear weapons [1], there is a pressing need for both...Detection System ( Bio -Rad Laboratories, Hercules CA) on 96-well microtiter plates with optical caps. Reactions were performed in a total volume of 50 µL... antigen -induced arthritis by dehydroepiandrosterone (DHEA). Inflamm Res 2004;53:189–98. 56. Auci D, Nicoletti F, Mangano K et al. Anti-inflammatory and

Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer.

PubMed

Kannaiyan, Radhamani; Shanmugam, Muthu K; Sethi, Gautam

2011-04-01

Identification of active constituents and their molecular targets from traditional medicine is an enormous opportunity for modern pharmacology. Celastrol is one such compound that was originally identified from traditional Chinese medicine (Thunder of God Vine) almost three decades ago and generally used for the treatment of inflammatory and auto-immune diseases. Celastrol has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. The anti-inflammatory effects of this triterpene have been demonstrated in animal models of different inflammatory diseases, including arthritis, Alzheimer's disease, asthma, and systemic lupus erythematosus. This triterpene has also been found to inhibit the proliferation of a variety of tumor cells and suppress tumor initiation, promotion and metastasis in various cancer models in vivo. Celastrol's ability to modulate the expression of pro-inflammatory cytokines, MHC II, HO-1, iNOS, NF-κB, Notch-1, AKT/mTOR, CXCR4, TRAIL receptors DR4 and DR5, CHOP, JNK, VEGF, adhesion molecules, proteasome activity, topoisomerase II, potassium channels, and heat shock response has been reported. This review describes the various molecular targets of celastrol, cellular responses to celastrol, and animal studies with celastrol in cancer and other inflammatory disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota.

PubMed

Shanmugam, Nanda Kumar N; Trebicka, Estela; Fu, Ling-Lin; Shi, Hai Ning; Cherayil, Bobby J

2014-08-01

States of chronic inflammation such as inflammatory bowel disease are often associated with dysregulated iron metabolism and the consequent development of an anemia that is caused by maldistribution of iron. Abnormally elevated expression of the hormone hepcidin, the central regulator of systemic iron homeostasis, has been implicated in these abnormalities. However, the mechanisms that regulate hepcidin expression in conditions such as inflammatory bowel disease are not completely understood. To clarify this issue, we studied hepcidin expression in mouse models of colitis. We found that dextran sulfate sodium-induced colitis inhibited hepcidin expression in wild-type mice but upregulated it in IL-10-deficient animals. We identified two mechanisms contributing to this difference. Firstly, erythropoietic activity, as indicated by serum erythropoietin concentrations and splenic erythropoiesis, was higher in the wild-type mice, and pharmacologic inhibition of erythropoiesis prevented colitis-associated hepcidin downregulation in these animals. Secondly, the IL-10 knockout mice had higher expression of multiple inflammatory genes in the liver, including several controlled by STAT3, a key regulator of hepcidin. The results of cohousing and fecal transplantation experiments indicated that the microbiota was involved in modulating the expression of hepcidin and other STAT3-dependent hepatic genes in the context of intestinal inflammation. Our observations thus demonstrate the importance of erythropoietic activity and the microbiota in influencing hepcidin expression during colitis and provide insight into the dysregulated iron homeostasis seen in inflammatory diseases. Copyright © 2014 by The American Association of Immunologists, Inc.

Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases

PubMed Central

Sallam, Nada

2016-01-01

Despite the wealth of epidemiological and experimental studies indicating the protective role of regular physical activity/exercise training against the sequels of aging and cardiovascular diseases, the molecular transducers of exercise/physical activity benefits are not fully identified but should be further investigated in more integrative and innovative approaches, as they bear the potential for transformative discoveries of novel therapeutic targets. As aging and cardiovascular diseases are associated with a chronic state of oxidative stress and inflammation mediated via complex and interconnected pathways, we will focus in this review on the antioxidant and anti-inflammatory actions of exercise, mainly exerted on adipose tissue, skeletal muscles, immune system, and cardiovascular system by modulating anti-inflammatory/proinflammatory cytokines profile, redox-sensitive transcription factors such as nuclear factor kappa B, activator protein-1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, antioxidant and prooxidant enzymes, and repair proteins such as heat shock proteins, proteasome complex, oxoguanine DNA glycosylase, uracil DNA glycosylase, and telomerase. It is important to note that the effects of exercise vary depending on the type, intensity, frequency, and duration of exercise as well as on the individual's characteristics; therefore, the development of personalized exercise programs is essential. PMID:26823952

Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases.

PubMed

Sallam, Nada; Laher, Ismail

2016-01-01

Despite the wealth of epidemiological and experimental studies indicating the protective role of regular physical activity/exercise training against the sequels of aging and cardiovascular diseases, the molecular transducers of exercise/physical activity benefits are not fully identified but should be further investigated in more integrative and innovative approaches, as they bear the potential for transformative discoveries of novel therapeutic targets. As aging and cardiovascular diseases are associated with a chronic state of oxidative stress and inflammation mediated via complex and interconnected pathways, we will focus in this review on the antioxidant and anti-inflammatory actions of exercise, mainly exerted on adipose tissue, skeletal muscles, immune system, and cardiovascular system by modulating anti-inflammatory/proinflammatory cytokines profile, redox-sensitive transcription factors such as nuclear factor kappa B, activator protein-1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, antioxidant and prooxidant enzymes, and repair proteins such as heat shock proteins, proteasome complex, oxoguanine DNA glycosylase, uracil DNA glycosylase, and telomerase. It is important to note that the effects of exercise vary depending on the type, intensity, frequency, and duration of exercise as well as on the individual's characteristics; therefore, the development of personalized exercise programs is essential.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases.

PubMed

Lin, T-H; Pajarinen, J; Lu, L; Nabeshima, A; Cordova, L A; Yao, Z; Goodman, S B

Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system. © 2017 Elsevier Inc. All rights reserved.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

PubMed Central

Lin, T.-h.; Pajarinen, J.; Lu, L.; Nabeshima, A.; Cordova, L.A.; Yao, Z.; Goodman, S.B.

2017-01-01

Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system. PMID:28215222

Potent anti-inflammatory effects of systemically-administered curcumin modulates periodontal disease in vivo

PubMed Central

Guimarães, Morgana R.; Coimbra, Leila S.; de Aquino, Sabrina Garcia; Spolidorio, Luis C.; Kirkwood, Keith L.; Junior, Carlos Rossa

2011-01-01

Background Curcumin is a plant-derived dietary spice with various biological activities, including anti-tumoral and anti-inflammatory. Its therapeutic applications have been studied in a variety of conditions, including rheumatoid arthritis, colon cancer and depression; but no studies evaluated the effects of curcumin on periodontal disease in vivo. Methods Experimental periodontal disease was induced in rats by placing cotton ligatures around both lower first molars. Curcumin was given to the rats intragastrically daily in two doses (30 and 100 mg/Kg) during 15 days. Control animals received ligatures but only the corn oil vehicle by gavage and no treatment negative control animals were included. Bone resorption was assessed by microcomputer tomography and the inflammatory status was evaluated by stereometric analysis. RT-qPCR and ELISA were used to determine the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and prostaglandin E2 (PGE2) synthase on the gingival tissues. Modulation of p38 mitogen-activated protein kinase (MAPK) and NK-kB activation was assessed by western blot. Results Bone resorption was effectively induced in the experimental period, but it was not affected by either dose of curcumin. Curcumin effectively inhibited cytokine gene expression at mRNA and protein levels and dose-dependently inhibited activation of NF-kB in the gingival tissues. p38 MAPK activation was not inhibited by curcumin. Curcumin-treated animals also presented a marked reduction on the inflammatory cell infiltrate and increased collagen content and fibroblastic cell numbers. Conclusions Curcumin did not prevent alveolar bone resorption, but its potent anti-inflammatory effect suggests it may have a therapeutic potential in periodontal diseases. PMID:21306385

Potent anti-inflammatory effects of systemically administered curcumin modulate periodontal disease in vivo.

PubMed

Guimarães, M R; Coimbra, L S; de Aquino, S G; Spolidorio, L C; Kirkwood, K L; Rossa, C

2011-04-01

Curcumin is a plant-derived dietary spice with various biological activities, including anticarcinogenic and anti-inflammatory effects. Its therapeutic applications have been studied in a variety of conditions, including rheumatoid arthritis, colon cancer and depression, but no studies have evaluated the effects of curcumin on periodontal disease in vivo. Experimental periodontal disease was induced in rats by placing cotton ligatures around both lower first molars. Curcumin was given to the rats by the intragastric route daily at two dosages (30 and 100 mg/kg) for 15 d. Control animals received ligatures but only the corn oil vehicle by gavage, and no treatment-negative control animals were included. Bone resorption was assessed by micro-computed tomography, and the inflammatory status was evaluated by stereometric analysis. Both RT-qPCR and ELISA were used to determine the expression of interleukin-6, tumor necrosis factor-α and prostaglandin E(2) synthase in the gingival tissues. Modulation of p38 MAPK and nuclear factor-κB activation were assessed by western blotting. Bone resorption was effectively induced in the experimental period, but it was not affected by either dose of curcumin. Curcumin effectively inhibited cytokine gene expression at both the mRNA and the protein level and produced a dose-dependent inhibition of the activation of nuclear factor-κB in the gingival tissues. Activation of p38 MAPK was not inhibited by curcumin. Curcumin-treated animals also presented a marked reduction of the inflammatory cell infiltrate and increased collagen content and fibroblastic cell numbers. Curcumin did not prevent alveolar bone resorption, but its potent anti-inflammatory effect suggests that it may have a therapeutic potential in periodontal diseases. © 2011 John Wiley & Sons A/S.

Effects of glutamine, taurine and their association on inflammatory pathway markers in macrophages.

PubMed

Sartori, Talita; Galvão Dos Santos, Guilherme; Nogueira-Pedro, Amanda; Makiyama, Edson; Rogero, Marcelo Macedo; Borelli, Primavera; Fock, Ricardo Ambrósio

2018-06-01

The immune system is essential for the control and elimination of infections, and macrophages are cells that act as important players in orchestrating the various parts of the inflammatory/immune response. Amino acids play important role in mediating functionality of the inflammatory response, especially mediating macrophages functions and cytokines production. We investigated the influence of glutamine, taurine and their association on the modulation of inflammatory pathway markers in macrophages. The RAW 264.7 macrophage cell line was cultivated in the presence of glutamine and taurine and proliferation rates, cell viability, cell cycle phases, IL-1α, IL-6, IL-10 and TNF-α as well as H 2 O 2 production and the expression of the transcription factor, NFκB, and its inhibitor, IκBα, were evaluated. Our results showed an increase in viable cells and increased proliferation rates of cells treated with glutamine concentrations over 2 mM, as well as cells treated with both glutamine and taurine. The cell cycle showed a higher percentage of cells in the phases S, G2 and M when they were treated with 2 or 10 mM glutamine, or with glutamine and taurine in cells stimulated with lipopolysaccharide. The pNFκB/NFκB showed reduced ratio expression when cells were treated with 10 mM of glutamine or with glutamine in association with taurine. These conditions also resulted in reduced TNF-α, IL-1α and H 2 O 2 production, and higher production of IL-10. These findings demonstrate that glutamine and taurine are able to modulate macrophages inflammatory pathways, and that taurine can potentiate the effects of glutamine, illustrating their immunomodulatory properties.

Interleukin-10 Is Produced by a Specific Subset of Taste Receptor Cells and Critical for Maintaining Structural Integrity of Mouse Taste Buds

PubMed Central

Chai, Jinghua; Zhou, Minliang; Simon, Nirvine; Huang, Liquan

2014-01-01

Although inflammatory responses are a critical component in defense against pathogens, too much inflammation is harmful. Mechanisms have evolved to regulate inflammation, including modulation by the anti-inflammatory cytokine interleukin-10 (IL-10). Previously we have shown that taste buds express various molecules involved in innate immune responses, including the proinflammatory cytokine tumor necrosis factor (TNF). Here, using a reporter mouse strain, we show that taste cells also express the anti-inflammatory cytokine IL-10. Remarkably, IL-10 is produced by only a specific subset of taste cells, which are different from the TNF-producing cells in mouse circumvallate and foliate taste buds: IL-10 expression was found exclusively in the G-protein gustducin-expressing bitter receptor cells, while TNF was found in sweet and umami receptor cells as reported previously. In contrast, IL-10R1, the ligand-binding subunit of the IL-10 receptor, is predominantly expressed by TNF-producing cells, suggesting a novel cellular hierarchy for regulating TNF production and effects in taste buds. In response to inflammatory challenges, taste cells can increase IL-10 expression both in vivo and in vitro. These findings suggest that taste buds use separate populations of taste receptor cells that coincide with sweet/umami and bitter taste reception to modulate local inflammatory responses, a phenomenon that has not been previously reported. Furthermore, IL-10 deficiency in mice leads to significant reductions in the number and size of taste buds, as well as in the number of taste receptor cells per taste bud, suggesting that IL-10 plays critical roles in maintaining structural integrity of the peripheral gustatory system. PMID:24523558

Substance P prevents development of proliferative vitreoretinopathy in mice by modulating TNF-α

PubMed Central

Yoo, Kyungsang; Son, Bo Kwon; Kim, Suna; Son, Youngsook; Yu, Seung-Young

2017-01-01

Purpose Proliferative vitreoretinopathy (PVR) is an inflammatory fibrotic disease resulting from the inflammatory milieu after retinal detachment, which can prevent retinal healing. This study aimed to elucidate the effect of substance P (SP) on retinal degeneration caused by retinal detachment in vivo and to examine the role of SP in the tumor necrosis factor-alpha (TNF-α)-induced epithelial-mesenchymal transition (EMT) of human RPE cells in vitro. Methods PVR-like retinal damage was induced by intravitreally injecting dispase into mice, and SP was systemically injected twice a week for 3 weeks. Histological analysis and cytokine profile with enzyme-linked immunosorbent assay (ELISA) were performed. The direct effect of SP on induction of EMT in vitro was studied by adding SP to TNF-α-treated ARPE-19 cells and then evaluating the change in the characteristics of the epithelial and mesenchymal cells. Results Dispase injection led to a PVR-like retinal condition, demonstrating an inflammatory response with disruption of RPE interaction within 1 week and severe destruction with enfolding within 3 weeks after the dispase injection. The inflammatory environment promoted apoptosis and migration of fibroblast-like cells in the retinal layer, which can cause fibrotic disease, such as PVR. However, SP treatment suppressed early inflammatory responses by reducing TNF-α and elevating interleukin-10 (IL-10), with cell death and the appearance of fibroblastic cells inhibited and the progression of retinal degeneration obviously delayed. Moreover, SP ameliorated TNF-α-induced EMT of the RPE and directly prevented fibrotic change in the RPE. Conclusions This study revealed that SP can block apoptosis and EMT due to retinal inflammation and inhibit the development of PVR. This effect most likely occurred by modulating the secretion and action of TNF-α.. PMID:29296073

Interleukin-10 is produced by a specific subset of taste receptor cells and critical for maintaining structural integrity of mouse taste buds.

PubMed

Feng, Pu; Chai, Jinghua; Zhou, Minliang; Simon, Nirvine; Huang, Liquan; Wang, Hong

2014-02-12

Although inflammatory responses are a critical component in defense against pathogens, too much inflammation is harmful. Mechanisms have evolved to regulate inflammation, including modulation by the anti-inflammatory cytokine interleukin-10 (IL-10). Previously we have shown that taste buds express various molecules involved in innate immune responses, including the proinflammatory cytokine tumor necrosis factor (TNF). Here, using a reporter mouse strain, we show that taste cells also express the anti-inflammatory cytokine IL-10. Remarkably, IL-10 is produced by only a specific subset of taste cells, which are different from the TNF-producing cells in mouse circumvallate and foliate taste buds: IL-10 expression was found exclusively in the G-protein gustducin-expressing bitter receptor cells, while TNF was found in sweet and umami receptor cells as reported previously. In contrast, IL-10R1, the ligand-binding subunit of the IL-10 receptor, is predominantly expressed by TNF-producing cells, suggesting a novel cellular hierarchy for regulating TNF production and effects in taste buds. In response to inflammatory challenges, taste cells can increase IL-10 expression both in vivo and in vitro. These findings suggest that taste buds use separate populations of taste receptor cells that coincide with sweet/umami and bitter taste reception to modulate local inflammatory responses, a phenomenon that has not been previously reported. Furthermore, IL-10 deficiency in mice leads to significant reductions in the number and size of taste buds, as well as in the number of taste receptor cells per taste bud, suggesting that IL-10 plays critical roles in maintaining structural integrity of the peripheral gustatory system.

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson's Disease and Amyotrophic Lateral Sclerosis.

PubMed

Roser, Anna-Elisa; Tönges, Lars; Lingor, Paul

2017-01-01

Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration. Activation of the Rho kinase (ROCK) pathway appears to be instrumental for the modulation of the microglial phenotype: increased ROCK activity in microglia mediates mechanisms of the inflammatory response and is associated with improved motility, increased production of reactive oxygen species (ROS) and release of inflammatory cytokines. Recently, several studies suggested inhibition of ROCK signaling as a promising treatment option for neurodegenerative diseases. In this review article, we discuss the contribution of microglial activity and phenotype switch to the pathophysiology of Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases without disease-modifying treatment options. Furthermore, we describe how ROCK inhibition can influence the microglial phenotype in disease models and explore ROCK inhibition as a future treatment option for PD and ALS.

Concomitant administration of fluoxetine and amantadine modulates the activity of peritoneal macrophages of rats subjected to a forced swimming test.

PubMed

Roman, Adam; Rogóz, Zofia; Kubera, Marta; Nawrat, Dominika; Nalepa, Irena

2009-01-01

Recent studies show that administration of a non-competitive NMDA receptor antagonist, amantadine (AMA), potentiates the action of antidepressant drugs. Since antidepressants may modulate functioning of the immune system and activation of a pro-inflammatory response in depressive disorders is frequently reported, the aim of the present study was to examine whether a combined administration of AMA and the antidepressant, fluoxetine (FLU), to rats subsequently subjected to a forced swimming test (FST) modifies the parameters of macrophage activity, directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and synthesis of nitric oxide (NO). We found that 10 mg/kg AMA and 10 mg/kg FLU, ineffective in FST for antidepressant-like activity when administered alone, increased the ARG/NO ratio in macrophages when administered concomitantly. This effect was accompanied by a decrease of cellular adherence. Concurrently, the basal metabolic activity of the cells measured with reduction of resazurin, and intracellular host defense as assessed by a synthesis of superoxide anion, were not affected by such antidepressive treatment. Our data indicate that co-administration of AMA and FLU decreases the pro-inflammatory properties of macrophages and causes a redirection of immune response toward anti-inflammatory activity, as one can anticipate in the case of an effective antidepressive treatment.

Enhancement of Anti-Inflammatory Activity of Curcumin Using Phosphatidylserine-Containing Nanoparticles in Cultured Macrophages.

PubMed

Wang, Ji; Kang, Yu-Xia; Pan, Wen; Lei, Wan; Feng, Bin; Wang, Xiao-Juan

2016-06-20

Macrophages are one kind of innate immune cells, and produce a variety of inflammatory cytokines in response to various stimuli, such as oxidized low density lipoprotein found in the pathogenesis of atherosclerosis. In this study, the effect of phosphatidylserine on anti-inflammatory activity of curcumin-loaded nanostructured lipid carriers was investigated using macrophage cultures. Different amounts of phosphatidylserine were used in the preparation of curcumin nanoparticles, their physicochemical properties and biocompatibilities were then compared. Cellular uptake of the nanoparticles was investigated using a confocal laser scanning microscope and flow cytometry analysis in order to determine the optimal phosphatidylserine concentration. In vitro anti-inflammatory activities were evaluated in macrophages to test whether curcumin and phosphatidylserine have interactive effects on macrophage lipid uptake behavior and anti-inflammatory responses. Here, we showed that macrophage uptake of phosphatidylserine-containing nanostructured lipid carriers increased with increasing amount of phosphatidylserine in the range of 0%-8%, and decreased when the phosphatidylserine molar ratio reached over 12%. curcumin-loaded nanostructured lipid carriers significantly inhibited lipid accumulation and pro-inflammatory factor production in cultured macrophages, and evidently promoted release of anti-inflammatory cytokines, when compared with curcumin or phosphatidylserine alone. These results suggest that the delivery system using PS-based nanoparticles has great potential for efficient delivery of drugs such as curcumin, specifically targeting macrophages and modulation of their anti-inflammatory functions.

Anthocyanins as inflammatory modulators and the role of the gut microbiota.

PubMed

Morais, Carina Almeida; de Rosso, Veridiana Vera; Estadella, Débora; Pisani, Luciana Pellegrini

2016-07-01

The health benefits of consuming fruits that are rich in polyphenols, especially anthocyanins, have been the focus of recent in vitro and in vivo investigations. Thus, greater attention is being directed to the reduction of the inflammatory process associated with the intestinal microbiota and the mechanism underlying these effects because the microbiota has been closely associated with the metabolism of these compounds in the gastrointestinal tract. Further interest lies in the ability of these metabolites to modulate the growth of specific intestinal bacteria. Thus, this review examines studies involving the action of the anthocyanins that are present in many fruits and their effect in the modulating the inflammatory process associated with the interaction between the host and the gut microbiota. The findings of both in vitro and in vivo studies suggest a potential antiinflammatory effect of these compounds, which seem to inhibit activation of the signaling pathway mediated by the transcription factor NFκB. This effect is associated with modulation of a beneficial gut microbiota, particularly an increase in Bifidobacterium strains. Copyright © 2015 Elsevier Inc. All rights reserved.

Prostanoids and their receptors that modulate dendritic cell-mediated immunity.

PubMed

Gualde, Norbert; Harizi, Hedi

2004-08-01

Dendritic cells (DC) are essential for the initiation of immune responses by capturing, processing and presenting antigens to T cells. In addition to their important role as professional APC, they are able to produce immunosuppressive and pro-inflammatory prostanoids from arachidonic acid (AA) by the action of cyclooxygenase (COX) enzymes. In an autocrine and paracrine fashion, the secreted lipid mediators subsequently modulate the maturation, cytokine production, Th-cell polarizing ability, chemokine receptor expression, migration, and apoptosis of these extremely versatile APC. The biological actions of prostanoids, including their effects on APC-mediated immunity and acute inflammatory responses, are exerted by G protein-coupled receptors on plasma membrane. Some COX metabolites act as anti-inflammatory lipid mediators by binding to nuclear receptors and modulating DC functions. Although the role of cytokines in DC function has been studied extensively, the effects of prostanoids on DC biology have only recently become the focus of investigation. This review summarizes the current knowledge about the role of prostanoids and their receptors in modulating DC function and the subsequent immune responses.

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies.

PubMed

Dante, Mariane de Cássia Lima; Borgheti-Cardoso, Livia Neves; Fantini, Marcia Carvalho de Abreu; Praça, Fabíola Silva Garcia; Medina, Wanessa Silva Garcia; Pierre, Maria Bernadete Riemma; Lara, Marilisa Guimarães

2018-03-01

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction: understanding mechanisms of the actions of rifaximin in selected gastrointestinal diseases.

PubMed

DuPont, H L

2016-01-01

Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile. © 2015 John Wiley & Sons Ltd.

Rational modulation of the innate immune system for neuroprotection in ischemic stroke

PubMed Central

Amantea, Diana; Micieli, Giuseppe; Tassorelli, Cristina; Cuartero, María I.; Ballesteros, Iván; Certo, Michelangelo; Moro, María A.; Lizasoain, Ignacio; Bagetta, Giacinto

2015-01-01

The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction. PMID:25972779

Influence of toll-like receptor 4 gene variants and plasma fatty acid profile on systemic inflammation: A population-based cross-sectional study.

PubMed

Norde, Marina Maintinguer; Oki, Erica; Carioca, Antonio A F; Castro, Inar A; Souza, José M P; Marchioni, Dirce M L; Fisberg, Regina M; Rogero, Marcelo M

2017-03-01

The aim of this study was to investigate the interaction of toll-like receptor 4 (TLR4) gene single nucleotide polymorphism (SNP) and plasma fatty acid (FA) profile in modulating risk for systemic inflammation. In all, 262 adult (19-59 y) participants of the Health Survey of São Paulo met the inclusion criteria. Anthropometric parameters, blood pressure, plasma inflammatory biomarker concentration, and fatty acid profile were measured and four SNPs of the TLR4 gene (rs4986790, rs4986791, rs11536889, and rs5030728) were genotyped. Multivariate cluster analysis was performed to stratify individuals based on levels of 11 plasma inflammatory biomarkers into two groups: inflammatory (INF) and noninflammatory (NINF). No association was found between any of the SNPs studied and systemic inflammation. The INF cluster had higher palmitic acid levels (P = 0.039) and estimated stearoyl coenzyme A desaturase activity (P = 0.045) and lower polyunsaturated fatty acid (P = 0.011), ω-6 fatty acid (P = 0.018), arachidonic acid (P = 0.002) levels, and estimated δ-5 desaturase activity (P = 0.025) compared with the NINF cluster. Statistically significant interaction between rs11536889 and arachidonic acid/eicosapentaenoic acid (AA/EPA) ratio (P = 0.034) was found to increase the odds of belonging to the INF cluster when individuals had the variant allele C and were at the higher percentile of AA/EPA plasma ratio. Plasma fatty acid profile modulated the odds of belonging to the INF cluster depending on genotypes of TRL4 gene polymorphisms. Copyright © 2016 Elsevier Inc. All rights reserved.

Selective Granulocyte and Monocyte Apheresis as a Non-Pharmacological Option for Patients with Inflammatory Bowel Disease

PubMed Central

C. Leitner, Gerda; Worel, Nina; Vogelsang, Harald

2012-01-01

Ulcerative colitis and Crohn's disease are the two most prevalent inflammatory bowel diseases. In both cases, the medically refractory and steroid-dependent type presents a therapeutic challenge. To help resolve this problem, a mainly Japanese team developed a new therapeutic option. There are two systems, both of which are able to selectively remove the main mediators of the disease, namely the activated pro-inflammatory cytokine-producing granulocytes and monocytes/macrophages, from the patient's blood circulation (GMA = granulocyte monocyte apheresis). One of the two systems is the Adacolumn® (Immunoresearch Laboratories, Takasaki, Japan) consisting of the ADA-monitor and a single-use column, which contains approximately 35,000 cellulose acetate beads. The exact mode of action is not yet sufficiently understood, but however, a modulation of the immune system takes place. As a result, less pro-inflammatory cytokines are released. Furthermore, the production of anti-inflammatory interleukin-1 receptor antagonist is increased, and the apoptosis of granulocytes boosted. The decreased LECAM-1-expression on leukocytes impedes the leukotaxis to the inflamed tissue, and CD10-negative immature granulocytes appear in the peripheral blood. Another effect to be mentioned is the removal of the peripheral dendritic cells and the leachate of regulatory T cells (T-regs). The second system is the Cellsorba® FX Filter (Asahi Medical, Tokyo, Japan). The range of efficiency, the indication, and the procedure are very similar to the Adacolumn. Solely the additional removal of lymphocytes can possibly limit the implementation since lymphopenia can increase the risk of autoimmune disease. Both systems provide a low-risk therapy with few adverse reactions. ASFA recommendations for GMA in inflammatory bowel disease are 2B due to the fact that not enough randomized double-blind studies are available to proof the efficacy of this treatment. PMID:22969694

The hygiene theory harnessing helminths and their ova to treat autoimmunity.

PubMed

Ben-Ami Shor, Dana; Harel, Michal; Eliakim, Rami; Shoenfeld, Yehuda

2013-10-01

The incidence of autoimmune diseases is increasing in Western countries, possibly due to the improved sanitary conditions and reduced exposure to infections in childhood (the hygiene hypothesis). There is an ongoing debate whether infection prevents or precipitates autoimmune diseases. Various helminths species used in several animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. At present the scientific data is based mostly on experimental animal models; however, there is an increasing body of evidence in a number of clinical trials being conducted. Herein we review several clinical trials evaluating the anti-inflammatory effects of helminths and assessing their association with different autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and autoimmune liver diseases. We also describe the common pathways by which helminths induce immune modulation and the key changes observed in the host immune system following exposure to helminths. These common pathways include the inhibition of IFN-γ and IL-17 production, promotion of IL-4, IL-10 and TGF-β release, induction of CD4(+) T cell FoxP3(+) expression, and generation of regulatory macrophages, dendritic cells, and B cells. Helminths products are becoming significant candidates for anti-inflammatory agents in this context. However, further research is needed for synthetic analogues of helminths' potent products that mimic the parasite-mediated immunomodulation effect.

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.

Macrolides: a promising pharmacologic therapy for chronic obstructive pulmonary disease

PubMed Central

Qiu, Shilin; Zhong, Xiaoning

2016-01-01

Chronic inflammation plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, there are no effective anti-inflammatory pharmacologic therapies available for COPD so far. Recent evidence suggests that an immunologic mechanism has a role in the pathogenesis of COPD. Macrolides possess anti-inflammatory and immune-modulating effects may be helpful in the treatment of COPD. Several clinical studies have shown that long-term use of macrolides reduces the frequency of COPD exacerbations. However, the subgroups that most effectively respond to long-term treatment of macrolides still need to be determined. The potential adverse events to individuals and the microbial resistance in community populations raises great concern on the long-term use of macrolides. Thus, novel macrolides have anti-inflammatory and immuno-modulating effects, but without antibiotic effects, and are promising as an anti-inflammatory agent for the treatment of COPD. In addition, the combination of macrolides and other anti-inflammatory pharmacologic agents may be a new strategy for the treatment of COPD. PMID:28030992

Modulation of sphingosine-1-phosphate in inflammatory bowel disease.

PubMed

Peyrin-Biroulet, Laurent; Christopher, Ronald; Behan, Dominic; Lassen, Cheryl

2017-05-01

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs. Sphingosine-1-phosphate (S1P), a membrane-derived lysophospholipid signaling molecule, is implicated in a vast array of physiological and pathophysiological processes, primarily via extracellular activation of S1P1-S1P5 receptors. S1P1, S1P4 and S1P5 are involved in regulation of the immune system, while S1P2 and S1P3 may be associated with cardiovascular, pulmonary, and theoretical cancer-related risks. Targeting S1P receptors for inflammatory conditions has been successful in clinical trials leading to approval of the non-selective S1P modulator, fingolimod, for relapsing forms of multiple sclerosis. However, the association of this non-selective S1P modulator with serious adverse events provides the rationale for developing more selective S1P receptor modulators. Until recently, three S1P modulators with differing selectivity for S1P receptors were in clinical development for IBD: ozanimod (RPC1063), etrasimod (APD334) and amiselimod (MT-1303). The development of amiselimod has been stopped as Biogen are currently focusing on other drugs in its portfolio. Following encouraging results from the Phase 2 TOUCHSTONE trial, a Phase 3 trial of the S1P modulator ozanimod in patients with moderate-to-severe ulcerative colitis is ongoing. Etrasimod is also being tested in a phase 2 trial in ulcerative colitis. These pipeline medications can be administered orally and may avoid the formation of anti-drug antibodies that can lead to treatment failure with injectable biologic therapies for IBD. Data from ongoing clinical trials will establish the relationship between the selectivity of S1P modulators and their safety and efficacy in IBD, as well as their potential place in the clinical armamentarium for IBD. Copyright © 2017. Published by Elsevier B.V.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

PubMed Central

Kernbauer, Elisabeth; Hölzl, Markus A.; Hofer, Johannes; Gualdoni, Guido A.; Schmetterer, Klaus G.; Miftari, Fitore; Sobanov, Yury; Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Witzeneder, Nadine; Greiner, Georg; Ohradanova-Repic, Anna; Waidhofer-Söllner, Petra; Säemann, Marcus D.; Decker, Thomas

2017-01-01

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation. PMID:28742108

FOREIGN BODY REACTION TO BIOMATERIALS

PubMed Central

Anderson, James M.; Rodriguez, Analiz; Chang, David T.

2008-01-01

The foreign body reaction composed of macrophages and foreign body giant cells is the end-stage response of the inflammatory and wound healing responses following implantation of a medical device, prosthesis, or biomaterial. A brief, focused overview of events leading to the foreign body reaction is presented. The major focus of this review is on factors that modulate the interaction of macrophages and foreign body giant cells on synthetic surfaces where the chemical, physical, and morphological characteristics of the synthetic surface are considered to play a role in modulating cellular events. These events in the foreign body reaction include protein adsorption, monocyte/macrophage adhesion, macrophage fusion to form foreign body giant cells, consequences of the foreign body response on biomaterials, and cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells. Biomaterial surface properties play an important role in modulating the foreign body reaction in the first two to four weeks following implantation of a medical device, even though the foreign body reaction at the tissue/material interface is present for the in vivo lifetime of the medical device. An understanding of the foreign body reaction is important as the foreign body reaction may impact the biocompatibility (safety) of the medical device, prosthesis, or implanted biomaterial and may significantly impact short- and long-term tissue responses with tissue-engineered constructs containing proteins, cells, and other biological components for use in tissue engineering and regenerative medicine. Our perspective has been on the inflammatory and wound healing response to implanted materials, devices, and tissue-engineered constructs. The incorporation of biological components of allogeneic or xenogeneic origin as well as stem cells into tissue-engineered or regenerative approaches opens up a myriad of other challenges. An in depth understanding of how the immune system interacts with these cells and how biomaterials or tissue-engineered constructs influences these interactions may prove pivotal to the safety, biocompatibility, and function of the device or system under consideration. PMID:18162407

Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury

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

Peters, Esther, E-mail: esther.peters@radboudumc.n

Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n = 18) were subjected to renal ischemia (30 min) and reperfusion (I/R), or sham-operated. In a second model, rats (n = 18) received a 30 minmore » infusion of lipopolysaccharide (LPS; 2.5 mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000 U/kg) was administered intravenously (15 min before reperfusion, or 90 min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial. - Highlights: • Human recombinant alkaline phosphatase (recAP) is a potential new therapy for sepsis-associated acute kidney injury (AKI). • RecAP can modulate renal oxygenation and hemodynamics immediately following I/R-induced AKI. • RecAP did not modulate endotoxemia-induced changes in systemic hemodynamics and renal oxygenation. • RecAP did exert a clear renal protective anti-inflammatory effect in both models.« less

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.

Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance.

PubMed

Aroor, Annayya R; McKarns, Susan; Demarco, Vincent G; Jia, Guanghong; Sowers, James R

2013-11-01

Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. © 2013.

Inflammation and neuronal plasticity: a link between childhood trauma and depression pathogenesis.

PubMed

Cattaneo, Annamaria; Macchi, Flavia; Plazzotta, Giona; Veronica, Begni; Bocchio-Chiavetto, Luisella; Riva, Marco Andrea; Pariante, Carmine Maria

2015-01-01

During the past two decades, there has been increasing interest in understanding and characterizing the role of inflammation in major depressive disorder (MDD). Indeed, several are the evidences linking alterations in the inflammatory system to Major Depression, including the presence of elevated levels of pro-inflammatory cytokines, together with other mediators of inflammation. However, it is still not clear whether inflammation represents a cause or whether other factors related to depression result in these immunological effects. Regardless, exposure to early life stressful events, which represent a vulnerability factor for the development of psychiatric disorders, act through the modulation of inflammatory responses, but also of neuroplastic mechanisms over the entire life span. Indeed, early life stressful events can cause, possibly through epigenetic changes that persist over time, up to adulthood. Such alterations may concur to increase the vulnerability to develop psychopathologies. In this review we will discuss the role of inflammation and neuronal plasticity as relevant processes underlying depression development. Moreover, we will discuss the role of epigenetics in inducing alterations in inflammation-immune systems as well as dysfunction in neuronal plasticity, thus contributing to the long-lasting negative effects of stressful life events early in life and the consequent enhanced risk for depression. Finally we will provide an overview on the potential role of inflammatory system to aid diagnosis, predict treatment response, enhance treatment matching, and prevent the onset or relapse of Major Depression.

Effects of LPS-induced immune activation prior to trauma exposure on PTSD-like symptoms in mice.

PubMed

Deslauriers, Jessica; van Wijngaarde, Myrthe; Geyer, Mark A; Powell, Susan; Risbrough, Victoria B

2017-04-14

The prevalence of posttraumatic stress disorder (PTSD) is high in the armed services, with a rate up to 20%. Multiple studies have associated markers of inflammatory signaling prior to trauma with increased risk of PTSD, suggesting a potential role of the immune system in the development of this psychiatric disorder. One question that arises is if "priming" the immune system before acute trauma alters the stress response and increases enduring effects of trauma. We investigated the time course of inflammatory response to predator stress, a robust stressor that induces enduring PTSD-like behaviors, and the modulation of these effects via prior immune activation with the bacterial endotoxin, lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist. Mice exposed to predator stress exhibited decreased pro-/anti-inflammatory balance in the brain 6h after stress, suggesting that predator exposure acutely suppressed the immune system by increasing anti-inflammatory cytokines levels. Acute immune activation with LPS before a single predator stress did not alter the enduring avoidance behavior in stressed mice. Our findings suggest that acute inflammation, at least via TLR4 activation, is not sufficient to increase susceptibility for PTSD-like behaviors in this model. Future studies will examine if chronic inflammation is required to induce similar immune changes to those observed in PTSD patients in this model. Published by Elsevier B.V.

Nanoparticles that Communicate In Vivo to Amplify Tumour Targeting

PubMed Central

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2012-01-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability for communication to improve targeting in biological systems, such inflammatory cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘Signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally active the coagulation cascade to broadcast tumour location to clot-targeted ‘Receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed from multiple types of Signalling and Receiving modules, can transmit information via multiple molecular pathways in coagulation, can operate autonomously, and can target over 40-fold higher doses of chemotherapeutics to tumours than non-communicating controls. PMID:21685903

Nanoparticles that communicate in vivo to amplify tumour targeting

NASA Astrophysics Data System (ADS)

von Maltzahn, Geoffrey; Park, Ji-Ho; Lin, Kevin Y.; Singh, Neetu; Schwöppe, Christian; Mesters, Rolf; Berdel, Wolfgang E.; Ruoslahti, Erkki; Sailor, Michael J.; Bhatia, Sangeeta N.

2011-07-01

Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability of communication to improve targeting in biological systems, such as inflammatory-cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally activate the coagulation cascade to broadcast tumour location to clot-targeted ‘receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed of multiple types of signalling and receiving modules, can transmit information through multiple molecular pathways in coagulation, can operate autonomously and can target over 40 times higher doses of chemotherapeutics to tumours than non-communicating controls.

Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

PubMed Central

Thom, Vivien; Arumugam, Thiruma V.; Magnus, Tim; Gelderblom, Mathias

2017-01-01

Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg. PMID:28824617

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.

Relevance of chronic stress and the two faces of microglia in Parkinson’s disease

PubMed Central

Herrera, Antonio J.; Espinosa-Oliva, Ana M.; Carrillo-Jiménez, Alejandro; Oliva-Martín, María J.; García-Revilla, Juan; García-Quintanilla, Alberto; de Pablos, Rocío M.; Venero, José L.

2015-01-01

This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson’s disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD. PMID:26321913

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

PubMed Central

Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

2015-01-01

Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

Lipid Rafts in Mast Cell Biology

PubMed Central

Silveira e Souza, Adriana Maria Mariano; Mazucato, Vivian Marino; Jamur, Maria Célia; Oliver, Constance

2011-01-01

Mast cells have long been recognized to have a direct and critical role in allergic and inflammatory reactions. In allergic diseases, these cells exert both local and systemic responses, including allergic rhinitis and anaphylaxis. Mast cell mediators are also related to many chronic inflammatory conditions. Besides the roles in pathological conditions, the biological functions of mast cells include roles in innate immunity, involvement in host defense mechanisms against parasites, immunomodulation of the immune system, tissue repair, and angiogenesis. Despite their growing significance in physiological and pathological conditions, much still remains to be learned about mast cell biology. This paper presents evidence that lipid rafts or raft components modulate many of the biological processes in mast cells, such as degranulation and endocytosis, play a role in mast cell development and recruitment, and contribute to the overall preservation of mast cell structure and organization. PMID:21490812

West African Sorghum bicolor Leaf Sheaths Have Anti-Inflammatory and Immune-Modulating Properties In Vitro

PubMed Central

Benson, Kathleen F.; Beaman, Joni L.; Ou, Boxin; Okubena, Ademola; Okubena, Olajuwon

2013-01-01

Abstract The impact of chronic inflammatory conditions on immune function is substantial, and the simultaneous application of anti-inflammatory and immune modulating modalities has potential for reducing inflammation-induced immune suppression. Sorghum-based foods, teas, beers, and extracts are used in traditional medicine, placing an importance on obtaining an increased understanding of the biological effects of sorghum. This study examined selected anti-inflammatory and immune-modulating properties in vitro of Jobelyn™, containing the polyphenol-rich leaf sheaths from a West African variant of Sorghum bicolor (SBLS). Freshly isolated primary human polymorphonuclear (PMN) and mononuclear cell subsets were used to test selected cellular functions in the absence versus presence of aqueous and ethanol extracts of SBLS. Both aqueous and nonaqueous compounds contributed to reduced reactive oxygen species formation by inflammatory PMN cells, and reduced the migration of these cells in response to the inflammatory chemoattractant leukotriene B4. Distinct effects were seen on lymphocyte and monocyte subsets in cultures of peripheral blood mononuclear cells. The aqueous extract of SBLS triggered robust upregulation of the CD69 activation marker on CD3− CD56+ natural killer (NK) cells, whereas the ethanol extract of SBLS triggered similar upregulation of CD69 on CD3+ CD56+ NKT cells, CD3+ T lymphocytes, and monocytes. This was accompanied by many-fold increases in the chemokines RANTES/CCL5, Mip-1α/CCL3, and MIP-1β/CCL4. Both aqueous and nonaqueous compounds contribute to anti-inflammatory effects, combined with multiple effects on immune cell activation status. These observations may help suggest mechanisms of action that contribute to the traditional use of sorghum-based products, beverages, and extracts for immune support. PMID:23289787

Harnessing dendritic cells in inflammatory skin diseases

PubMed Central

Chu, Chung-Ching; Di Meglio, Paola; Nestle, Frank O.

2011-01-01

The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies. PMID:21295490

Biological activity of lactoferrin-functionalized biomimetic hydroxyapatite nanocrystals

PubMed Central

Nocerino, Nunzia; Fulgione, Andrea; Iannaccone, Marco; Tomasetta, Laura; Ianniello, Flora; Martora, Francesca; Lelli, Marco; Roveri, Norberto; Capuano, Federico; Capparelli, Rosanna

2014-01-01

The emergence of bacterial strains resistant to antibiotics is a general public health problem. Progress in developing new molecules with antimicrobial properties has been made. In this study, we evaluated the biological activity of a hybrid nanocomposite composed of synthetic biomimetic hydroxyapatite surface-functionalized by lactoferrin (LF-HA). We evaluated the antimicrobial, anti-inflammatory, and antioxidant properties of LF-HA and found that the composite was active against both Gram-positive and Gram-negative bacteria, and that it modulated proinflammatory and anti-inflammatory responses and enhanced antioxidant properties as compared with LF alone. These results indicate the possibility of using LF-HA as an antimicrobial system and biomimetic hydroxyapatite as a candidate for innovative biomedical applications. PMID:24623976

Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia.

PubMed

Johansson, Jenny U; Pradhan, Suraj; Lokteva, Ludmila A; Woodling, Nathaniel S; Ko, Novie; Brown, Holden D; Wang, Qian; Loh, Christina; Cekanaviciute, Egle; Buckwalter, Marion; Manning-Bog, Amy B; Andreasson, Katrin I

2013-10-02

Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2(lox/lox) mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.

Suppression of Inflammation with Conditional Deletion of the Prostaglandin E2 EP2 Receptor in Macrophages and Brain Microglia

PubMed Central

Johansson, Jenny U.; Pradhan, Suraj; Lokteva, Ludmila A.; Woodling, Nathaniel S.; Ko, Novie; Brown, Holden D.; Wang, Qian; Loh, Christina; Cekanaviciute, Egle; Buckwalter, Marion; Manning-Boğ, Amy B.

2013-01-01

Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP1–4 receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2lox/lox mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2lox/lox and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain. PMID:24089506

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.

Emergence of a metalloproteinase / phospholipase A2 axis of systemic inflammation

PubMed Central

Fernandez-Patron, Carlos; Leung, Dickson

2015-01-01

We review select aspects of the biology of matrix metalloproteinases (MMPs) with a focus on the modulation of inflammatory responses by MMP-2. MMP-2 is a zinc- and calcium-dependent endoprotease with substrates including extracellular matrix proteins, vasoactive peptides and chemokines. Humans and mice with MMP-2 deficiency exhibit a predominantly inflammatory phenotype. Recent research shows that MMP-2 deficient mice display elevated activity of a secreted phospholipase A2 in the heart. Additionally, MMP-2 deficient mice exhibit abnormally high prostaglandin E2 levels in various organs (i.e., the heart, brain and liver), signs of inflammation and exacerbated lipopolysaccharide-induced fever. We briefly review the biology of sPLA2 enzymes to propose the existence of a heart-centric MMP-2/sPLA2 axis of systemic inflammation. Moreover, we postulate that PLA2 activation is induced by chemokines, whose ability to signal inflammation is regulated in a tissue-specific fashion by MMPs. Thus, genetic and pharmacologically induced MMP-deficiencies can be expected to perturb PLA2-mediated inflammatory mechanisms. PMID:26491703

The role of chalcones in suppression of NF-κB-mediated inflammation and cancer.

PubMed

Yadav, Vivek R; Prasad, Sahdeo; Sung, Bokyung; Aggarwal, Bharat B

2011-03-01

Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2',4'-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin chalcone. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review. Copyright © 2010 Elsevier B.V. All rights reserved.

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

PubMed

Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

2017-08-08

The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Ecdysone mediates the development of immunity in the Drosophila embryo.

PubMed

Tan, Kiri Louise; Vlisidou, Isabella; Wood, Will

2014-05-19

Beyond their role in cell metabolism, development, and reproduction, hormones are also important modulators of the immune system. In the context of inflammatory disorders, systemic administration of pharmacological doses of synthetic glucocorticoids (GCs) is widely used as an anti-inflammatory treatment [1, 2]. However, not all actions of GCs are immunosuppressive, and many studies have suggested that physiological concentrations of GCs can have immunoenhancing effects [3-7]. For a more comprehensive understanding of how steroid hormones regulate immunity and inflammation, a simple in vivo system is required. The Drosophila embryo has recently emerged as a powerful model system to study the recruitment of immune cells to sterile wounds [8] and host-pathogen dynamics [9]. Here we investigate the immune response of the fly embryo to bacterial infections and find that the steroid hormone 20-hydroxyecdysone (20-HE) can regulate the quality of the immune response and influence the resolution of infection in Drosophila embryos. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality.

PubMed

Osuchowski, Marcin F; Welch, Kathy; Siddiqui, Javed; Remick, Daniel G

2006-08-01

Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1beta, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1-5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-alpha (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6-28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.

Host modulation therapy: An indispensable part of perioceutics

PubMed Central

Gulati, Minkle; Anand, Vishal; Govila, Vivek; Jain, Nikil

2014-01-01

Traditionally, only antimicrobials have been used as the chemotherapeutic modality for the treatment of periodontitis. Though bacteria are the primary etiologic factors of periodontal diseases, yet the extent and severity of tissue destruction seen in periodontitis is determined by the host immuno-inflammatory response to these bacteria. This increasing awareness and knowledge of the host-microbial interaction in periodontal pathogenesis has presented the opportunity for exploring new therapeutic strategies for periodontitis by means of targeting host response via host-modulating agents. This has lead to the emergence of the field of “Perioceutics” i.e. the use of parmacotherapeutic agents including antimicrobial therapy as well as host modulatory therapy for the management of periodontitis. These host-modulating agents used as an adjunct tip the balance between periodontal health and disease progression in the direction of a healing response. In this article the host-modulating role of various systemically and locally delivered perioceutic agents will be reviewed. PMID:25024538

Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion.

PubMed

Mohagheghi, Fatemeh; Khalaj, Leila; Ahmadiani, Abolhassan; Rahmani, Behrouz

2013-04-01

Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia-reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis.

PubMed

Lupia, Enrico; Pigozzi, Luca; Goffi, Alberto; Hirsch, Emilio; Montrucchio, Giuseppe

2014-11-07

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis

PubMed Central

Lupia, Enrico; Pigozzi, Luca; Goffi, Alberto; Hirsch, Emilio; Montrucchio, Giuseppe

2014-01-01

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis. PMID:25386068

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

IL-17A alone weakly affects the transcriptome of intestinal epithelial cells but strongly modulates the TNF-α-induced expression of inflammatory mediators and inflammatory bowel disease susceptibility genes.

PubMed

Friedrich, Matthias; Diegelmann, Julia; Beigel, Florian; Brand, Stephan

2014-09-01

In contrast to anti-TNF-α antibodies, anti-IL-17A antibodies lacked clinical efficacy in a trial with patients suffering from Crohn's disease. We therefore analyzed how IL-17A modulates the inflammatory response elicited by TNF-α in intestinal epithelial cells (IEC). Target mRNA levels in IEC and colonic biopsies were assessed by RNA microarray and quantitative real-time PCR. Signaling pathways were analyzed using receptor neutralization and pharmacological inhibitors. Target protein levels were determined by immunoblotting. Microarray analysis demonstrated that IL-17A alone is a weak inducer of gene expression in IEC (29 regulated transcripts), but significantly affected the TNF-α-induced expression of 547 genes, with strong amplification of proinflammatory chemokines and cytokines (>200-fold increase of CCL20, CXCL1, and CXCL8). Interestingly, IL-17A differentially modulated the TNF-α-induced expression of several inflammatory bowel disease susceptibility genes in IEC (increase of JAK2 mRNA, decrease of FUT2, ICAM1, and LTB mRNA). Negative regulation of ICAM-1 by IL-17A was verified on protein level. The significance of these findings is emphasized by inflamed lesions of patients with inflammatory bowel disease demonstrating significant correlations (P < 0.01, Rho, 0.57-0.85) for JAK2, ICAM1, and LTB mRNA with IL17A and TNF mRNA. Our study demonstrates the modulation of inflammatory bowel disease susceptibility gene mRNA in IEC as a novel important property of IL-17A. Given the weak impact of sole IL-17A stimulation on IEC target gene expression, our study provides an important explanation for the lack of clinical efficacy of sole IL-17A neutralization, but suggests a beneficial effect of combined IL-17A/TNF-α that is currently in clinical development.

HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats.

PubMed

Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

2015-01-01

HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.

HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats

PubMed Central

Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

2015-01-01

Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. Methods The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. Results HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. Conclusion HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders. PMID:26125554

Immune-Modulating Perspectives for Low Frequency Electromagnetic Fields in Innate Immunity

PubMed Central

Rosado, Maria Manuela; Simkó, Myrtill; Mattsson, Mats-Olof; Pioli, Claudio

2018-01-01

In recent years, the effects of electromagnetic fields (EMFs) on the immune system have received a considerable interest, not only to investigate possible negative health impact but also to explore the possibility to favorably modulate immune responses. To generate beneficial responses, the immune system should eradicate pathogens while “respecting” the organism and tolerating irrelevant antigens. According to the current view, damage-associated molecules released by infected or injured cells, or secreted by innate immune cells generate danger signals activating an immune response. These signals are also relevant to the subsequent activation of homeostatic mechanisms that control the immune response in pro- or anti-inflammatory reactions, a feature that allows modulation by therapeutic treatments. In the present review, we describe and discuss the effects of extremely low frequency (ELF)-EMF and pulsed EMF on cell signals and factors relevant to the activation of danger signals and innate immunity cells. By discussing the EMF modulating effects on cell functions, we envisage the use of EMF as a therapeutic agent to regulate immune responses associated with wound healing. PMID:29632855

Immune-Modulating Perspectives for Low Frequency Electromagnetic Fields in Innate Immunity.

PubMed

Rosado, Maria Manuela; Simkó, Myrtill; Mattsson, Mats-Olof; Pioli, Claudio

2018-01-01

In recent years, the effects of electromagnetic fields (EMFs) on the immune system have received a considerable interest, not only to investigate possible negative health impact but also to explore the possibility to favorably modulate immune responses. To generate beneficial responses, the immune system should eradicate pathogens while "respecting" the organism and tolerating irrelevant antigens. According to the current view, damage-associated molecules released by infected or injured cells, or secreted by innate immune cells generate danger signals activating an immune response. These signals are also relevant to the subsequent activation of homeostatic mechanisms that control the immune response in pro- or anti-inflammatory reactions, a feature that allows modulation by therapeutic treatments. In the present review, we describe and discuss the effects of extremely low frequency (ELF)-EMF and pulsed EMF on cell signals and factors relevant to the activation of danger signals and innate immunity cells. By discussing the EMF modulating effects on cell functions, we envisage the use of EMF as a therapeutic agent to regulate immune responses associated with wound healing.

Co-incubation of PMN and CaCo-2 cells modulates inflammatory potential.

PubMed

Schaefer, M B; Schaefer, C A; Hecker, M; Morty, R E; Witzenrath, M; Seeger, W; Mayer, K

2017-05-20

Polymorphonuclear granulocytes (PMN) are activated in inflammatory reactions. Intestinal epithelial cells are relevant for maintaining the intestinal barrier. We examined interactions of PMN and intestinal epithelial cell-like CaCo-2 cells to elucidate their regulation of inflammatory signalling and the impact of cyclooxygenase (COX), nitric oxide (NO) and platelet-activating factor (PAF). Human PMN and CaCo-2 cells, separately and in co-incubation, were stimulated with the calcium ionophore A23187 or with N-Formyl-methionyl-leucyl-phenylalanin (fMLP) that activates PMN only. Human neutrophil elastase (HNE) and respiratory Burst were measured. To evaluate the modulation of inflammatory crosstalk we applied inhibitors of COX (acetyl salicylic acid; ASA), NO-synthase (N-monomethyl-L-arginin; L-NMMA), and the PAF-receptor (WEB2086). Unstimulated, co-incubation of CaCo-2 cells and PMN led to significantly reduced Burst and elevated HNE as compared to PMN. After stimulation with A23187, co-incubation resulted in an inhibition of Burst and HNE. Using fMLP co-incubation failed to modulate Burst but increased HNE. Without stimulation, all three inhibitors abolished the effect of co-incubation on Burst but did not change HNE.  ASA partly prevented modulation of Burst L-NMMA and WEB2086 did not change Burst but abolished mitigation of HNE. Without stimulation, co-incubation reduced Burst and elevated HNE. Activation of PMN and CaCo-2 cells by fMLP as compared to A23187 resulted in a completely different pattern of Burst and HNE, possibly due to single vs. dual cell activation. Anti-inflammatory effect of co-incubation might in part be due to due to COX-signalling governing Burst whereas NO- and PAF-dependent signalling seemed to control HNE release.

Protective effect of vitamin E in an animal model of LPS-induced inflammation.

PubMed

Mayorga, M; Iborra, A; Estany, S; Martínez, P

2004-12-01

Many sterility outcomes may be associated to the presence of an inflammatory response that would lead to an inability of the endometrium to support implantation and maintain viable embryos. We have established an animal model of inflammation in which the systemic administration of lipopolysaccharyde (LPS) results in a low embryo implantation rate. The purpose of this work was to investigate the effect of the inflammatory agent LPS on embryo viability and to verify the ability of vitamin E to modulate the inflammatory effect of LPS on embryo viability. For pre-implantation studies B6CBAF1 mice, which were intraperitoneally inoculated with LPS (4-10 mg/kg), were used. Mice were also treated with vitamin E (4-10 mg/kg) before or after LPS injection. Embryos were obtained from the oviduct after each treatment. The LPS produces a decrease in the number of pre-implantational embryos in a concentration dependent manner. The LPS effect can be partially reversed or prevented by vitamin E. Preliminary results show that inflammatory cytokines are secreted by intraperitoneal macrophages in LPS treated mice. Our results demonstrate the ability of vitamin E to avoid an inflammatory environment and to allow viability of embryos. (c) Blackwell Munksgaard, 2004

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

Sympathetic Nervous System Modulation of Inflammation and Remodeling in the Hypertensive Heart

PubMed Central

Levick, Scott P.; Murray, David B.; Janicki, Joseph S.; Brower, Gregory L.

2010-01-01

Chronic activation of the sympathetic nervous system (SNS) is a key component of cardiac hypertrophy and fibrosis. However, previous studies have provided evidence to also implicate inflammatory cells, including mast cells, in the development of cardiac fibrosis. The current study investigated the potential interaction of cardiac mast cells with the SNS. Eight week old male SHR were sympathectomized to establish the effect of the SNS on cardiac mast cell density, myocardial remodeling and cytokine production in the hypertensive heart. Age-matched WKY served as controls. Cardiac fibrosis and hypertension were significantly attenuated and left ventricular mass normalized while cardiac mast cell density was markedly increased in sympathectomized SHR. Sympathectomy normalized myocardial levels of IFN-γ, IL-6 and IL-10, but had no effect on IL-4. The effect of norepinephrine and substance P on isolated cardiac mast cell activation was investigated as potential mechanisms of interaction between the two. Only substance P elicited mast cell degranulation. Substance P was also shown to induce the production of angiotensin II by a mixed population of isolated cardiac inflammatory cells, including mast cells, lymphocytes and macrophages. These results demonstrate the ability of neuropeptides to regulate inflammatory cell function, providing a potential mechanism by which the SNS and afferent nerves may interact with inflammatory cells in the hypertensive heart. PMID:20048196

Sphingosine kinase inhibition alleviates endothelial permeability induced by thrombin and activated neutrophils.

PubMed

Itagaki, Kiyoshi; Zhang, Qin; Hauser, Carl J

2010-04-01

Inflammation and microvascular thrombosis are interrelated causes of acute lung injury in the systemic inflammatory response syndrome. Neutrophils (polymorphonuclear neutrophil [PMN]) and endothelial cells (EC) activated by systemic inflammatory response syndrome interact to increase pulmonary vascular permeability, but the interactions between PMN and EC are difficult to study. Recently, we reported that sphingosine 1-phosphate is a second messenger eliciting store-operated calcium entry (SOCE) in response to inflammatory agonists in both PMN and EC. Store-operated calcium entry is therefore a target mechanism for the therapeutic modulation of inflammatory PMN-EC interactions. Here, we isolated, modeled, and studied the effects of pharmacologic SOCE inhibition using real-time systems to monitor EC permeability after exposure to activated PMN. We created systems to continuously assess permeability of human pulmonary artery endothelial cells and human microvascular endothelial cells from lung. Endothelial cells show increased permeability after challenge by activated PMN. Such permeability increases can be attenuated by exposure of the cocultures to sphingosine kinase (SK) inhibitors (SKI-2, N,N-dimethylsphingosine [DMS]) or Ca2+ entry inhibitors (Gd3+, MRS-1845). Human microvascular endothelial cells from lung pretreated with SKI-2 or DMS showed decreased permeability when later exposed to activated PMN. Likewise, when PMNs were activated with thapsigargin (TG) in the presence of SKI-2, DMS, Gd, or MRS-1845, their ability to cause EC permeability subsequently was reduced. SKI-2 also inhibited the activation of human pulmonary artery ECs by thrombin. These studies will provide a firm mechanistic foundation for understanding how systemic SOCE inhibition may be used to prevent acute lung injury in vivo.

Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Disease in Rat Collagen-Induced Arthritis

PubMed Central

Levine, Yaakov A.; Koopman, Frieda A.; Faltys, Michael; Caravaca, April; Bendele, Alison; Zitnik, Ralph; Vervoordeldonk, Margriet J.; Tak, Paul Peter

2014-01-01

Introduction The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model. Methods Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed. Results Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01). Conclusions The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders. PMID:25110981

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.

IL-30 (IL27p28) alleviates sepsis via modulation of cytokine profiles produced by NKT cells

PubMed Central

Yan, Jun; Mitra, Abhisek; Hu, Jiemiao; Cutrera, Jeffery J; Xia, Xueqing; Doetschman, Thomas; Gagea, Mihai; Mishra, Lopa; Li, Shulin

2016-01-01

Background & Aims Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulted from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. Methods Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL-30 (p28)−/−, IL10−/−, and CD1d−/− mice. Results Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer–like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon–gamma and tumor necrosis factor–alpha in IL-30–treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS-stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. Conclusions IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell–mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT. PMID:26767500

Morinda citrifolia lipid transfer protein 1 exhibits anti-inflammatory activity by modulation of pro- and anti-inflammatory cytokines.

PubMed

Campos, Dyély C O; Costa, Andrea S; Luz, Patrícia B; Soares, Pedro M G; Alencar, Nylane M N; Oliveira, Hermógenes D

2017-10-01

Previous reports have demonstrated that a thermostable lipid transfer protein isolated from noni seeds (McLTP 1 ; 9.4kDa) displays anti-nociceptive and anti-inflammatory activities. This work aimed to investigate the underlying mechanisms of the anti-inflammatory activity of McLTP 1 in mice. The protein was solubilised in sterile saline (0.9% NaCl) immediately before the treatment of mice by oral or intraperitoneal routes at doses of 8mg/kg. Given orally or intraperitoneally, McLTP 1 significantly inhibited (p<0.05) cell migration in experimental models of carrageenan-induced peritonitis and the formation of paw oedema induced by carrageenan and dextran. Additionally, McLTP 1 demonstrated the ability to significantly inhibit the production of the cytokines IL-1β, IL-6, and TNF-α (p<0.05) and to promote an increase in the production of the anti-inflammatory cytokine IL-10. The treatment of mice with McLTP 1 by the oral or i.p route reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury. This study suggested that the observed anti-inflammatory effects of McLTP 1 can be related to modulation of pro- and anti-inflammatory cytokine levels. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of nuclear factor-κB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents

PubMed Central

Gupta, Subash C; Kim, Ji Hye; Kannappan, Ramaswamy; Reuter, Simone; Dougherty, Patrick M; Aggarwal, Bharat B

2011-01-01

Cancer is a disease characterized by dysregulation of multiple genes and is associated with symptoms such as cachexia, anorexia, fatigue, depression, neuropathic pain, anxiety, cognitive impairment, sleep disorders and delirium (acute confusion state) in medically ill patients. These symptoms are caused by either the cancer itself or the cancer treatment. During the past decade, increasing evidence has shown that the dysregulation of inflammatory pathways contributes to the expression of these symptoms. Cancer patients have been found to have higher levels of proinflammatory cytokines such as interleukin-6. The nuclear factor (NF)- κB is a major mediator of inflammatory pathways. Therefore, anti-inflammatory agents that can modulate the NF-κB activation and inflammatory pathways may have potential in improving cancer-related symptoms in patients. Because of their multitargeting properties, low cost, low toxicity and immediate availability, natural agents have gained considerable attention for prevention and treatment of cancer-related symptoms. How NF-κB and inflammatory pathways contribute to cancer-related symptoms is the focus of this review. We will also discuss how nutritional agents such as curcumin, genistein, resveratrol, epigallocatechin gallate and lycopene can modulate inflammatory pathways and thereby reduce cancer-related symptoms in patients. PMID:21565893

Lactodifucotetraose, a human milk oligosaccharide, attenuates platelet function and inflammatory cytokine release.

PubMed

Newburg, David S; Tanritanir, Ayse C; Chakrabarti, Subrata

2016-07-01

Human milk strongly quenches inflammatory processes in vitro, and breastfed infants have lower incidence of inflammatory diseases than those fed artificially. Platelets from neonates, in contrast to those from adults, are less responsive to platelet agonists such as collagen, thrombin, ADP, and epinephrine. Breastfed infants absorb oligosaccharides intact from the human milk in their gut to the circulation. This study was to determine whether these oligosaccharides can attenuate platelet function and platelet secretion of pro-inflammatory proteins, and to identify the active component. The natural mixture of oligosaccharides from human milk and pure individual human milk oligosaccharides were tested for their ability to modulate responses of platelets isolated from human blood following exposure to thrombin, ADP, and collagen. Human milk and the natural mixture of human milk oligosaccharides inhibited platelet release of inflammatory proteins. Of the purified human milk oligosaccharides tested, only lactodifucotetraose (LDFT) significantly inhibited thrombin induced release of the pro-inflammatory proteins RANTES and sCD40L. LDFT also inhibited platelet adhesion to a collagen-coated surface, as well as platelet aggregation induced by ADP or collagen. These data indicate that LDFT may help modulate hemostasis by suppressing platelet-induced inflammatory processes in breastfed infants. This activity suggests further study of LDFT for its potential as a therapeutic agent in infants and adults.

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

PubMed

Huang, Chunxia; Irwin, Michael Garnet; Wong, Gordon Tin Chun; Chang, Raymond Chuen Chung

2018-05-17

Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice

PubMed Central

Bagdas, Deniz; Targowska-Duda, Katarzyna M.; López, Jhon J.; Perez, Edwin G.; Arias, Hugo R.; Damaj, M. Imad

2016-01-01

BACKGROUND Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant induced inflammatory pain, and the chronic constriction injury–induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective α7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid–induced aversion by using the conditioned place aversion test. RESULTS We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by α7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective α7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid induced aversion in the conditioned place aversion assay. CONCLUSIONS These findings suggest that the administration of PAM-2, a new α7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain. PMID:26280585

Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia.

PubMed

Hamzei Taj, Somayyeh; Kho, Widuri; Aswendt, Markus; Collmann, Franziska M; Green, Claudia; Adamczak, Joanna; Tennstaedt, Annette; Hoehn, Mathias

2016-12-01

Mononuclear phagocytes respond to ischemic stroke dynamically, undergoing an early anti-inflammatory and protective phenotype followed by the pro-inflammatory and detrimental type. These dual roles of microglia/macrophages suggest the need of subtle adjustment of their polarization state instead of broad suppression. The most abundant brain-specific miRNA, miR-124, promotes neuronal differentiation but can also modulate microglia activation and keeps them in a quiescent state. We addressed whether the intracerebral injection of miR-124 in a mouse model of ischemic stroke before or after the peak phase of the pro-inflammatory polarization modifies the pro-/anti- inflammatory balance. In the sub-acute phase, 48 h after stroke, liposomated miR-124 shifted the predominantly pro-inflammatory polarized microglia/macrophages toward the anti-inflammatory phenotype. The altered immune response improved neurological deficit at day 6 after stroke. When miR-124 was injected 10 days after stroke, the pro-/anti- inflammatory ratio was still significantly reduced although to a lower degree and had no effect on recovery at day 14. This study indicates that miR-124 administration before the peak of the pro-inflammatory process of stroke is most effective in support of increasing the rehabilitation opportunity in the sub-acute phases of stroke. Our findings highlight the important role of immune cells after stroke and the therapeutic relevance of their polarization balance.

Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis.

PubMed

Kodithuwakku, Nandani Darshika; Pan, Min; Zhu, Yi-lin; Zhang, Yan-yan; Feng, Yi-dong; Fang, Wei-rong; Li, Yun-man

2013-12-12

Shuang-Qi gout capsule is a traditional Chinese medicine prescription, which has been used in the treatment of joint pain, inflammation and gout arthritis. This study evaluates anti-inflammatory and antinociceptive effects of Shuang-Qi gout capsule and its modulation of pro-inflammatory cytokines with special reference to gout arthritis. Anti-inflammatory effect of Shuang-Qi gout capsule was investigated bymice tail-flick response, acetic acid induced writhing response, Xylene-induced auricle inflammation and the hind paw volume of the monosodium urate (MSU) crystal induced rats with different time durations. To investigate the effects on gout arthritis, ankle joint of rats induced by MSU crystals and assessed for edema and histopathological changes. In vitro, prepared serum was incubated with urate crystal induced HUVE cells and the release of TNF-α and IL-1β determined by ELISA. Shuang-Qi gout capsule showed significant and dose dependent anti-inflammatory effect via reducing edema and pain, throughout all the models. The high dose of Shuang-Qi gout capsule and Indomethacin significantly attenuated the edema. Histopathological results showed that high and medium dose of Shuang-Qi gout capsule and Indomethacin reduced gouty joint inflammatory features, while the high dose of Shuang-Qi gout capsule showed a better therapeutic effect. High and medium dose of Shuang-Qi gout capsule significantly reduced the release of TNF-α and IL-1β (p<0.05). Shuang-Qi gout capsule can effectively inhibit the inflammation, analgesia, through the modulation of emission of pro-inflammatory cytokines and the curative effect is dose dependent. Conversely, these MSU induced in vivo and in vitro studies of Shuang-Qi gout capsule suggest that, Shuang-Qi gout capsule may be a potential agent for treatment in gouty arthritis. © 2013 Published by Elsevier Ireland Ltd.

Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases

PubMed Central

Layne, Joseph; Majkova, Zuzana; Smart, Eric J.; Toborek, Michal; Hennig, Bernhard

2010-01-01

Dietary intervention strategies have proven to be an effective means of decreasing several risk factors associated with the development of atherosclerosis. Endothelial cell dysfunction influences vascular inflammation and is involved in promoting the earliest stages of lesion formation. Caveolae are lipid raft microdomains abundant within the plasma membrane of endothelial cells and are responsible for mediating receptor-mediated signal transduction. Caveolae have been implicated in the regulation of enzymes associated with several key signaling pathways capable of determining intracellular redox status. Diet and plasma-derived nutrients may modulate an inflammatory outcome by interacting with and altering caveolae-associated cellular signaling. For example, omega-3 fatty acids and several polyphenolics have been shown to improve endothelial cell function by decreasing the formation of ROS and increasing NO bioavailability, events associated with altered caveolae composition. Thus, nutritional modulation of caveolae-mediated signaling events may provide an opportunity to ameliorate inflammatory signaling pathways capable of promoting the formation of vascular diseases, including atherosclerosis. PMID:21292468

Mesenchymal Stem Cells Modulate Differentiation of Myeloid Progenitor Cells During Inflammation.

PubMed

Amouzegar, Afsaneh; Mittal, Sharad K; Sahu, Anuradha; Sahu, Srikant K; Chauhan, Sunil K

2017-06-01

Mesenchymal stem cells (MSCs) possess distinct immunomodulatory properties and have tremendous potential for use in therapeutic applications in various inflammatory diseases. MSCs have been shown to regulate pathogenic functions of mature myeloid inflammatory cells, such as macrophages and neutrophils. Intriguingly, the capacity of MSCs to modulate differentiation of myeloid progenitors (MPs) to mature inflammatory cells remains unknown to date. Here, we report the novel finding that MSCs inhibit the expression of differentiation markers on MPs under inflammatory conditions. We demonstrate that the inhibitory effect of MSCs is dependent on direct cell-cell contact and that this intercellular contact is mediated through interaction of CD200 expressed by MSCs and CD200R1 expressed by MPs. Furthermore, using an injury model of sterile inflammation, we show that MSCs promote MP frequencies and suppress infiltration of inflammatory cells in the inflamed tissue. We also find that downregulation of CD200 in MSCs correlates with abrogation of their immunoregulatory function. Collectively, our study provides unequivocal evidence that MSCs inhibit differentiation of MPs in the inflammatory environment via CD200-CD200R1 interaction. Stem Cells 2017;35:1532-1541. © 2017 AlphaMed Press.

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases

PubMed Central

Sanmarco, Liliana Maria; Eberhardt, Natalia; Ponce, Nicolás Eric; Cano, Roxana Carolina; Bonacci, Gustavo; Aoki, Maria Pilar

2018-01-01

Macrophages are the primary immune cells that reside within the myocardium, suggesting that these mononuclear phagocytes are essential in the orchestration of cardiac immunity and homeostasis. Independent of the nature of the injury, the heart triggers leukocyte activation and recruitment. However, inflammation is harmful to this vital terminally differentiated organ with extremely poor regenerative capacity. As such, cardiac tissue has evolved particular strategies to increase the stress tolerance and minimize the impact of inflammation. In this sense, growing evidences show that mononuclear phagocytic cells are particularly dynamic during cardiac inflammation or infection and would actively participate in tissue repair and functional recovery. They respond to soluble mediators such as metabolites or cytokines, which play central roles in the timing of the intrinsic cardiac stress response. During myocardial infarction two distinct phases of monocyte influx have been identified. Upon infarction, the heart modulates its chemokine expression profile that sequentially and actively recruits inflammatory monocytes, first, and healing monocytes, later. In the same way, a sudden switch from inflammatory macrophages (with microbicidal effectors) toward anti-inflammatory macrophages occurs within the myocardium very shortly after infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy. While in sterile injury, healing response is necessary to stop tissue damage; during an intracellular infection, the anti-inflammatory milieu in infected hearts would promote microbial persistence. The balance of mononuclear phagocytic cells seems to be also dynamic in atherosclerosis influencing plaque initiation and fate. This review summarizes the participation of mononuclear phagocyte system in cardiovascular diseases, keeping in mind that the immune system evolved to promote the reestablishment of tissue homeostasis following infection/injury, and that the effects of different mediators could modulate the magnitude and quality of the immune response. The knowledge of the effects triggered by diverse mediators would serve to identify new therapeutic targets in different cardiovascular pathologies. PMID:29375564

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases.

PubMed

Sanmarco, Liliana Maria; Eberhardt, Natalia; Ponce, Nicolás Eric; Cano, Roxana Carolina; Bonacci, Gustavo; Aoki, Maria Pilar

2017-01-01

Macrophages are the primary immune cells that reside within the myocardium, suggesting that these mononuclear phagocytes are essential in the orchestration of cardiac immunity and homeostasis. Independent of the nature of the injury, the heart triggers leukocyte activation and recruitment. However, inflammation is harmful to this vital terminally differentiated organ with extremely poor regenerative capacity. As such, cardiac tissue has evolved particular strategies to increase the stress tolerance and minimize the impact of inflammation. In this sense, growing evidences show that mononuclear phagocytic cells are particularly dynamic during cardiac inflammation or infection and would actively participate in tissue repair and functional recovery. They respond to soluble mediators such as metabolites or cytokines, which play central roles in the timing of the intrinsic cardiac stress response. During myocardial infarction two distinct phases of monocyte influx have been identified. Upon infarction, the heart modulates its chemokine expression profile that sequentially and actively recruits inflammatory monocytes, first, and healing monocytes, later. In the same way, a sudden switch from inflammatory macrophages (with microbicidal effectors) toward anti-inflammatory macrophages occurs within the myocardium very shortly after infection with Trypanosoma cruzi , the causal agent of Chagas cardiomyopathy. While in sterile injury, healing response is necessary to stop tissue damage; during an intracellular infection, the anti-inflammatory milieu in infected hearts would promote microbial persistence. The balance of mononuclear phagocytic cells seems to be also dynamic in atherosclerosis influencing plaque initiation and fate. This review summarizes the participation of mononuclear phagocyte system in cardiovascular diseases, keeping in mind that the immune system evolved to promote the reestablishment of tissue homeostasis following infection/injury, and that the effects of different mediators could modulate the magnitude and quality of the immune response. The knowledge of the effects triggered by diverse mediators would serve to identify new therapeutic targets in different cardiovascular pathologies.

Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

PubMed

Brattsand, R; Linden, M

1996-01-01

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.

Local and systemic immune mechanisms underlying the anti-colitis effects of the dairy bacterium Lactobacillus delbrueckii.

PubMed

Santos Rocha, Clarissa; Gomes-Santos, Ana Cristina; Garcias Moreira, Thais; de Azevedo, Marcela; Diniz Luerce, Tessalia; Mariadassou, Mahendra; Longaray Delamare, Ana Paula; Langella, Philippe; Maguin, Emmanuelle; Azevedo, Vasco; Caetano de Faria, Ana Maria; Miyoshi, Anderson; van de Guchte, Maarten

2014-01-01

Several probiotic bacteria have been proposed for treatment or prevention of inflammatory bowel diseases (IBD), showing a protective effect in animal models of experimental colitis and for some of them also in human clinical trials. While most of these probiotic bacteria are isolated from the digestive tract, we recently reported that a Lactobacillus strain isolated from cheese, L. delbrueckii subsp. lactis CNRZ327 (Lb CNRZ327), also possesses anti-inflammatory effects in vitro and in vivo, demonstrating that common dairy bacteria may be useful in the treatment or prevention of IBD. Here, we studied the mechanisms underlying the protective effects of Lb CNRZ327 in vivo, in a mouse dextran sodium sulfate (DSS) colitis model. During colitis, Lb CNRZ327 modulated the production of TGF-β, IL-6, and IL-12 in colonic tissue and of TGF-β and IL-6 in the spleen, and caused an expansion of CD4+Foxp3+ regulatory T cells in the cecal lymph nodes. Moreover, a strong tendency to CD4+Foxp3+ expansion was also observed in the spleen. The results of this study for the first time show that orally administered dairy lactobacilli can not only modulate mucosal but also systemic immune responses and constitute an effective treatment of IBD.

Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

PubMed Central

Fritz, Michael; Klawonn, Anna M.; Nilsson, Anna; Singh, Anand Kumar; Zajdel, Joanna; Björk Wilhelms, Daniel; Lazarus, Michael; Löfberg, Andreas; Jaarola, Maarit; Örtegren Kugelberg, Unn; Billiar, Timothy R.; Hackam, David J.; Sodhi, Chhinder P.; Breyer, Matthew D.; Jakobsson, Johan; Schwaninger, Markus; Schütz, Günther; Rodriguez Parkitna, Jan; Saper, Clifford B.; Blomqvist, Anders; Engblom, David

2015-01-01

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation. PMID:26690700

A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram.

PubMed

Ho, Pei-Shen; Yeh, Yi-Wei; Huang, San-Yuan; Liang, Chih-Sung

2015-03-01

Depression is hypothesized to involve inflammatory processes, and identifying the key cytokines targeted by antidepressant drugs is critical for tailoring treatment to specific cases. However, investigating a limited number of cytokines at one time cannot provide a broad picture of antidepressant-associated immunomodulation. Cytokines act in a network where one could demonstrate pleiotropism, redundancy, synergy, and antagonism with other cytokine functions. This study was aimed at determining whether escitalopram functions as an anti-inflammatory agent and, if so, how it influences cytokine networks. A total of 24 healthy controls and 26 patients with clinical depression requiring inpatient treatment were recruited. A multiplex assay, an efficient tool to simultaneously measure 27 cytokines, was applied in patients with depression before and after 4-week escitalopram treatment. Healthy controls did not take escitalopram and completed cytokine analyses once. We demonstrated that escitalopram increased the levels of interleukin (IL)-1 receptor antagonist and IL-2. Moreover, escitalopram contributed to a shift toward T helper 2 responses and an increase in modulators of innate immunity, leading to a decrease of immune system activation, both innate and adaptive. We suggest that escitalopram modulates the balance of IL-1 and IL-1 receptor antagonist and improves the function and number of T regulatory cells. However, diverse conclusions could be drawn if only a few cytokines were assessed or different significance levels were used. Further studies should investigate a wide range of cytokines in a reliable and valid way, which is key to disentangling the effects of different antidepressants on inflammatory processes. Copyright © 2015 Elsevier Ltd. All rights reserved.

A β-Lactam Antibiotic Dampens Excitotoxic Inflammatory CNS Damage in a Mouse Model of Multiple Sclerosis

PubMed Central

Torres-Salazar, Delany; Bittner, Stefan; Zozulya, Alla L.; Weidenfeller, Christian; Kotsiari, Alexandra; Stangel, Martin; Fahlke, Christoph; Wiendl, Heinz

2008-01-01

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial “Excitatory Amino Acid Transporters” (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a β-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in “Myelin Oligodendrocyte Glycoprotein” (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFγ and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a β-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis. PMID:18773080

Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.

PubMed

Foresti, Roberta; Bains, Sandip K; Pitchumony, Tamil Selvi; de Castro Brás, Lisandra E; Drago, Filippo; Dubois-Randé, Jean-Luc; Bucolo, Claudio; Motterlini, Roberto

2013-10-01

The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 μM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-γ (INF-γ) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-α, PGE2 and nitrite) more strongly in cells challenged with INF-γ than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bifidobacterium breve - HT-29 cell line interaction: modulation of TNF-α induced gene expression.

PubMed

Boesten, R J; Schuren, F H J; Willemsen, L E M; Vriesema, A; Knol, J; De Vos, W M

2011-06-01

To provide insight in the molecular basis for intestinal host-microbe interactions, we determined the genome-wide transcriptional response of human intestinal epithelial cells following exposure to cells of Bifidobacterium breve. To select an appropriate test system reflecting inflammatory conditions, the responsiveness to TNF-α was compared in T84, Caco-2 and HT-29 cells. The highest TNF-α response was observed in HT-29 cells and this cell line was selected for exposure to the B. breve strains M-16V, NR246 and UCC2003. After one hour of bacterial pre-incubation followed by two hours of additional TNF-α stimulation, B. breve M-16V (86%), but to a much lesser extent strains NR246 (50%) or UCC2003 (32%), showed a strain-specific reduction of the HT-29 transcriptional response to the inflammatory treatment. The most important functional groups of genes that were transcriptionally suppressed by the presence of B. breve M-16V, were found to be involved in immune regulation and apoptotic processes. About 54% of the TNF-α induced genes were solely suppressed by the presence of B. breve M-16V. These included apoptosis-related cysteine protease caspase 7 (CASP7), interferon regulatory factor 3 (IRF3), amyloid beta (A4) precursor proteinbinding family A member 1 (APBA1), NADPH oxidase (NOX5), and leukemia inhibitory factor receptor (LIFR). The extracellular IL-8 concentration was determined by an immunological assay but did not change significantly, indicating that B. breve M-16V only partially modulates the TNF-α pathway. In conclusion, this study shows that B. breve strains modulate gene expression in HT-29 cells under inflammatory conditions in a strain-specific way.

Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.

PubMed

Kim, Jae Hwan; Kim, Jae Young; Mun, Chin Hee; Suh, Minah; Lee, Jong Eun

2017-10-01

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206 + & ED1 + cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.

Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats

PubMed Central

Kim, Jae Young; Mun, Chin Hee; Suh, Minah

2017-01-01

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype. PMID:29093636

Polyphenol supplementation as a complementary medicinal approach to treating inflammatory bowel disease.

PubMed

Biasi, F; Astegiano, M; Maina, M; Leonarduzzi, G; Poli, G

2011-01-01

Inflammatory bowel disease (IBD) comprises a group of idiopathic chronic intestinal inflammation syndromes that are very common in developed countries. It is characterized by intermittent episodes of clinical remission and relapse, with recurrent inflammatory injury that can lead to structural damage of the intestine. The uncontrolled intestinal immune response to bacterial antigens leads to the production of abundant cytokines and chemokines, by activated leukocytes and epithelial cells, which trigger inflammatory and oxidative reactions. The current treatment of IBD consists in long-term anti-inflammatory therapy that, however, does not exclude relapses and side effects, frequently resulting in surgical intervention. Polyphenols have been acknowledged to be anti-oxidant and anti-inflammatory and therefore, have been proposed as an alternative natural approach to prevent or treat chronic inflammatory diseases. Most studies have been in animal models of colitis, using chemical inducers or mice defective in anti-inflammatory mediators and in intestinal cell lines treated with pro-inflammatory cytokines or lipid oxidation products. These studies provide evidence that polyphenols can effectively modulate intestinal inflammation. They exert their effects by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector. Polyphenols may thus be considered able to prevent or delay the progression of IBD, especially because they reach higher concentrations in the gut than in other tissues. However, knowledge of the use of polyphenols in managing human IBD is still scanty, and further clinical studies should afford more solid evidence of their beneficial effects.

Modulation of obesity-induced inflammation by dietary fats: mechanisms and clinical evidence

PubMed Central

2014-01-01

Obesity plays a pivotal role in the development of low-grade inflammation. Dietary fatty acids are important modulators of inflammatory responses. Saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (PUFA) have been reported to exert pro-inflammatory effects. n-3 PUFA in particular, possess anti-inflammatory properties. Numerous clinical studies have been conducted over decades to investigate the impact of dietary fatty acids on inflammatory response in obese individuals, however the findings remained uncertain. High fat meals have been reported to increase pro-inflammatory responses, however there is limited evidence to support the role of individual dietary fatty acids in a postprandial state. Evidence in chronic studies is contradictory, the effects of individual dietary fatty acids deserves further attention. Weight loss rather than n-3 PUFA supplementation may play a more prominent role in alleviating low grade inflammation. In this context, the present review provides an update on the mechanistic insight and the influence of dietary fats on low grade inflammation, based on clinical evidence from acute and chronic clinical studies in obese and overweight individuals. PMID:24476102

Neutrophil Recruitment and Articular Hyperalgesia in Antigen-Induced Arthritis are Modulated by the Cholinergic Anti-Inflammatory Pathway.

PubMed

Kanashiro, Alexandre; Talbot, Jhimmy; Peres, Raphael S; Pinto, Larissa G; Bassi, Gabriel S; Cunha, Thiago M; Cunha, Fernando Q

2016-11-01

The cholinergic anti-inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuroimmune pathway on the progression of experimental arthritis. Using antigen-induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methylatropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed 1 week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur-tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis, providing a pre-clinical evidence of a potential therapeutic strategy for RA. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Leishmania infantum Induces the Release of sTREM-1 in Visceral Leishmaniasis

PubMed Central

Bomfim, Lays G. S.; Magalhães, Lucas S.; Santos-Filho, Marcello A. A.; Peres, Nalu T. A.; Corrêa, Cristiane B.; Tanajura, Diego M.; Silva, Angela M.; Lipscomb, Michael W.; Borges, Valéria M.; Jesus, Amélia R.; Almeida, Roque P.; de Moura, Tatiana R.

2017-01-01

Visceral leishmaniasis (VL) is a systemic transmissible disease that remains to be a major global health problem. The inflammatory response during VL is characterized by the release of several cytokines and other pro-inflammatory mediators. Triggering Receptor Expressed on Myeloid Cells (TREM) are a group of evolutionarily conserved membrane-bound surface receptors expressed on neutrophils and monocytes. Engagement of TREM-1 directs intracellular signaling events that drive cytokine production, degranulation, and phagocytosis. In certain inflammatory-associated diseases, TREM-1 can also be found as a soluble form (sTREM-1), which can negatively regulate TREM-1 receptor signaling. In these studies, we now find that high levels of circulating sTREM-1 correlate directly with VL disease severity. In particular, high levels of sTREM-1 were observed in non-survivor VL patients. Furthermore, these levels of sTREM-1 positively correlated with liver size and negatively correlated with leukocyte counts and hemoglobin concentration. Moreover, we found that neutrophils exposure in vitro to Leishmania infantum modulates TREM-1, DAP12, and IL-8 gene expression, while also increasing release of sTREM-1. Finally, results revealed that higher sTREM-1 levels are associated with increasing parasite ratio. Taken together, these studies suggest that L. infantum may modulate TREM-1 in neutrophils and high levels of this molecule is associated with severe VL. PMID:29201022

The therapeutic potential of exercise to treat cachexia.

PubMed

Lira, Fábio S; Antunes, Barbara de M M; Seelaender, Marília; Rosa Neto, José C

2015-12-01

To discuss the role of physical exercise in the attenuation of cancer cachexia-associated symptoms, and upon the outcome of chemotherapy, with special focus on the anti-inflammatory role of chronic exercise. The review addresses the recent findings regarding the positive effects of endurance and strength exercise training upon metabolic dysfunction, systemic inflammation and body composition alterations in the syndrome of cachexia. The employment of different exercise protocol strategies, in respect to intensity, duration, work load and in concomitance with pharmacological treatment is considered. Cachexia is a multifactorial wasting syndrome afflicting patients with cancer, chronic obstructive pulmonary disease, chronic heart failure, trauma, among other diseases. This condition markedly compromises the quality of life, treatment outcome and survival. Recent literature indicates an unequivocal role of chronic exercise in modulating cachexia and other cancer-associated dysfunctions. Exercise is proposed as a complementary treatment in cancer, and represents a function-preserving, anti-inflammatory and metabolism-modulating strategy with low cost, and high versatility and availability. Furthermore, exercise decreases cancer recurrence and presents a positive impact on public health management, reducing hospitalization and medication costs.

Elderberry and Elderflower Extracts, Phenolic Compounds, and Metabolites and Their Effect on Complement, RAW 264.7 Macrophages and Dendritic Cells

PubMed Central

Ho, Giang Thanh Thi; Wangensteen, Helle; Barsett, Hilde

2017-01-01

Modulation of complement activity and inhibition of nitric oxide (NO) production by macrophages and dendritic cells may have therapeutic value in inflammatory diseases. Elderberry and elderflower extracts, constituents, and metabolites were investigated for their effects on the complement system, and on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and murine dendritic D2SC/I cells. The EtOH crude extracts from elderberry and elderflower and the isolated anthocyanins and procyanidins possessed strong complement fixating activity and strong inhibitory activity on NO production in RAW cells and dendritic cells. Phenolic compounds in the range of 0.1–100 µM showed a dose-dependent inhibition of NO production, with quercetin, rutin, and kaempferol as the most potent ones. Among the metabolites, caffeic acid and 3,4-dihydroxyphenylacetic acid showed the strongest inhibitory effects on NO production in both cell lines, without having cytotoxic effect. Only 4-methylcatechol was cytotoxic at the highest tested concentration (100 µM). Elderberry and elderflower constituents may possess inflammatory modulating activity, which increases their nutritional value. PMID:28282861

Elderberry and Elderflower Extracts, Phenolic Compounds, and Metabolites and Their Effect on Complement, RAW 264.7 Macrophages and Dendritic Cells.

PubMed

Ho, Giang Thanh Thi; Wangensteen, Helle; Barsett, Hilde

2017-03-08

Modulation of complement activity and inhibition of nitric oxide (NO) production by macrophages and dendritic cells may have therapeutic value in inflammatory diseases. Elderberry and elderflower extracts, constituents, and metabolites were investigated for their effects on the complement system, and on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and murine dendritic D2SC/I cells. The EtOH crude extracts from elderberry and elderflower and the isolated anthocyanins and procyanidins possessed strong complement fixating activity and strong inhibitory activity on NO production in RAW cells and dendritic cells. Phenolic compounds in the range of 0.1-100 µM showed a dose-dependent inhibition of NO production, with quercetin, rutin, and kaempferol as the most potent ones. Among the metabolites, caffeic acid and 3,4-dihydroxyphenylacetic acid showed the strongest inhibitory effects on NO production in both cell lines, without having cytotoxic effect. Only 4-methylcatechol was cytotoxic at the highest tested concentration (100 µM). Elderberry and elderflower constituents may possess inflammatory modulating activity, which increases their nutritional value.

Impact of the cardiovascular system-associated adipose tissue on atherosclerotic pathology.

PubMed

Chistiakov, Dimitry A; Grechko, Andrey V; Myasoedova, Veronika A; Melnichenko, Alexandra A; Orekhov, Alexander N

2017-08-01

Cardiac obesity makes an important contribution to the pathogenesis of cardiovascular disease. One of the important pathways of this contribution is the inflammatory process that takes place in the adipose tissue. In this review, we consider the role of the cardiovascular system-associated fat in atherosclerotic cardiovascular pathology and a non-atherosclerotic cause of coronary artery disease, such as atrial fibrillation. Cardiovascular system-associated fat not only serves as the energy store, but also releases adipokines that control local and systemic metabolism, heart/vascular function and vessel tone, and a number of vasodilating and anti-inflammatory substances. Adipokine appears to play an important protective role in cardiovascular system. Under chronic inflammation conditions, the repertoire of signaling molecules secreted by cardiac fat can be altered, leading to a higher amount of pro-inflammatory messengers, vasoconstrictors, profibrotic modulators. This further aggravates cardiovascular inflammation and leads to hypertension, induction of the pathological tissue remodeling and cardiac fibrosis. Contemporary imaging techniques showed that epicardial fat thickness correlates with the visceral fat mass, which is an established risk factor and predictor of cardiovascular disease in obese subjects. However, this correlation is no longer present after adjustment for other covariates. Nevertheless, recent studies showed that pericardial fat volume and epicardial fat thickness can probably serve as a better indicator for atrial fibrillation. Copyright © 2017 Elsevier B.V. All rights reserved.

Peripherally administered orexin improves survival of mice with endotoxin shock

PubMed Central

Ogawa, Yasuhiro; Irukayama-Tomobe, Yoko; Murakoshi, Nobuyuki; Kiyama, Maiko; Ishikawa, Yui; Hosokawa, Naoto; Tominaga, Hiromu; Uchida, Shuntaro; Kimura, Saki; Kanuka, Mika; Morita, Miho; Hamada, Michito; Takahashi, Satoru; Hayashi, Yu; Yanagisawa, Masashi

2016-01-01

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin’s direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock. DOI: http://dx.doi.org/10.7554/eLife.21055.001 PMID:28035899

The acai flavonoid velutin is a potent anti-inflammatory agent: Blockade of LPS-mediated TNF-alpha and IL-6 production through inhibiting NF-kappa B activation and MAPK pathway

USDA-ARS?s Scientific Manuscript database

Recent studies have shown that some flavonoids are modulators for pro-inflammatory cytokine production. In this study, velutin, an unique flavone isolated from the pulp of acai fruit (Euterpe oleracea Mart.), was examined for its effects in reducing lipopolysaccharide-induced pro-inflammatory cytoki...

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.

Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study.

PubMed

Montón, C; Ewig, S; Torres, A; El-Ebiary, M; Filella, X; Rañó, A; Xaubet, A

1999-07-01

The aim of the study was to assess the potential role of glucocorticoids (GC) in modulating systemic and pulmonary inflammatory responses in mechanically ventilated patients with severe pneumonia. Twenty mechanically ventilated patients with pneumonia treated at a respiratory intensive care unit (RICU) of a 1,000-bed teaching hospital were prospectively studied. All patients had received prior antimicrobial treatment. Eleven patients received GC (mean+/-SD dose of i.v. methylprednisolone 677+/-508 mg for 9+/-7 days), mainly for bronchial dilatation. Serum and bronchoalveolar lavage fluid (BALF) tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and C-reactive protein levels were measured in all patients. The inflammatory response was attenuated in patients receiving GC, both systemically (IL-6 1,089+/-342 versus 630+/-385 pg x mL(-1), p=0.03; C-reactive protein 34+/-5 versus 19+/-5 mg x L(-1), p=0.04) and locally in BALF (TNF-alpha 118+/-50 versus 24+/-5 pg x mL(-1), p= 0.05; neutrophil count: 2.4+/-1.1 x 10(9) cells x L(-1) (93+/-3%) versus 1.9+/-1.8 x 10(9) cells x L(-1) (57+/-16%), p=0.03). Four of the 11 (36%) patients receiving GC died compared to six (67%) who were not receiving GC (p=0.37). The present pilot study suggests that glucocorticoids decrease systemic and lung inflammatory responses in mechanically ventilated patients with severe pneumonia receiving antimicrobial treatment.

Harnessing dendritic cells in inflammatory skin diseases.

PubMed

Chu, Chung-Ching; Di Meglio, Paola; Nestle, Frank O

2011-02-01

The skin immune system harbors a complex network of dendritic cells (DCs). Recent studies highlight a diverse functional specialization of skin DC subsets. In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms to ensure the maintenance of immune homeostasis, as well as in pathogenesis of chronic inflammation in the skin when excessive immune responses are initiated and unrestrained. Harnessing DCs by directly targeting DC-derived molecules or selectively modulate DC subsets is a convincing strategy to tackle inflammatory skin diseases. In this review we discuss recent advances underlining the functional specialization of skin DCs and discuss the potential implication for future DC-based therapeutic strategies. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in glial and neuronal cells of the central nervous system.

PubMed

Ramesh, Geeta; Martinez, Alejandra N; Martin, Dale S; Philipp, Mario T

2017-02-02

Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), affects both the central and peripheral nervous systems. Previously, we reported that in a model of acute LNB in rhesus monkeys, treatment with the anti-inflammatory drug dexamethasone significantly reduced both pleocytosis and levels of cerebrospinal fluid (CSF) immune mediators that were induced by Bb. Dexamethasone also inhibited the formation of inflammatory, neurodegenerative, and demyelinating lesions in the brain and spinal cord of these animals. In contrast, these signs were evident in the infected animals that were left untreated or in those that were treated with meloxicam, a non-steroidal anti-inflammatory drug. To address the differential anti-inflammatory effects of dexamethasone and meloxicam in the central nervous system (CNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in culture supernatants of rhesus frontal cortex (FC) explants, primary rhesus astrocytes and microglia, and human oligodendrocytes. We also ascertained the potential of dexamethasone to modulate Bb-induced apoptosis in rhesus FC explants. As meloxicam is a known COX-2 inhibitor, we evaluated whether meloxicam altered the levels of COX-2 as induced by live Bb in cell lysates of primary rhesus astrocytes and microglia. Dexamethasone but not meloxicam significantly reduced the levels of several Bb-induced immune mediators in culture supernatants of FC explants, astrocytes, microglia, and oligodendrocytes. Dexamethasone also had a protective effect on Bb-induced neuronal and oligodendrocyte apoptosis in rhesus FC explants. Further, meloxicam significantly reduced the levels of Bb-induced COX-2 in microglia, while both Bb and meloxicam were unable to alter the constitutive levels of COX-2 in astrocytes. These data indicate that dexamethasone and meloxicam have differential anti-inflammatory effects on Bb-induced inflammation in glial and neuronal cells of the CNS and help explain the in vivo findings of significantly reduced inflammatory mediators in the CSF and lack of inflammatory neurodegenerative lesions in the brain and spinal cord of Bb-infected animals that were treated with dexamethasone but not meloxicam. Signaling cascades altered by dexamethasone could serve as possible therapeutic targets for limiting CNS inflammation and tissue damage in LNB.

Temperature and Drug Treatments in Mevalonate Kinase Deficiency: An Ex Vivo Study

PubMed Central

Tricarico, Paola Maura; Piscianz, Elisa; Crovella, Sergio

2013-01-01

Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1β release. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD. PMID:24073415

Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis

PubMed Central

Wang, Shih-Min; Lei, Huan-Yao; Liu, Ching-Chuan

2012-01-01

Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema. PMID:22956971

The interplay between inflammatory cytokines and the endocannabinoid system in the regulation of synaptic transmission.

PubMed

Rossi, Silvia; Motta, Caterina; Musella, Alessandra; Centonze, Diego

2015-09-01

Excessive glutamate-mediated synaptic transmission and secondary excitotoxicity have been proposed as key determinants of neurodegeneration in many neurological diseases. Soluble mediators of inflammation have recently gained attention owing to their ability to enhance glutamate transmission and affect synaptic sensitivity to neurotransmitters. In the complex crosstalk between soluble immunoactive molecules and synapses, the endocannabinoid system (ECS) plays a central role, exerting an indirect neuroprotective action by inhibiting cytokine-dependent synaptic alterations, and a direct neuroprotective effect by limiting glutamate transmission and excitotoxic damage. On the other hand, the endocannabinoid (eCB)-mediated control of synaptic transmission is altered by proinflammatory cytokines with consequent effects in central nervous system (CNS) disorders. In this review, we summarize the interactions, at the pre- and postsynaptic level, between major inflammatory cytokines and the ECS. In addition, the behavioral and clinical consequences of the modulation of synaptic transmission during neuroinflammation are discussed. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.

PubMed

Lin, Yin Chiu; Kuo, Yu-Min; Liao, Pao-Chi; Cherng, Chianfang G; Su, Su-Wen; Yu, Lung

2007-04-30

Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.

Class II obese and healthy pregnant controls exhibit indistinguishable pro‐ and anti‐inflammatory immune responses to Caesarian section

PubMed Central

Graham, Caroline; Thorleifson, Mullein; Stefura, William P.; Funk, Duane J.

2017-01-01

Abstract Introduction Obesity during pregnancy is associated with meta‐inflammation and an increased likelihood of clinical complications. Surgery results in intense, acute inflammatory responses in any individual. Because obese individuals exhibit constitutive inflammatory responses and high rates of Caesarian section, it is important to understand the impact of surgery in such populations. Whether more pronounced pro‐inflammatory cytokine responses and/or counterbalancing changes in anti‐inflammatory immune modulators occurs is unknown. Here we investigated innate immune capacity in vivo and in vitro in non‐obese, term‐pregnant controls versus healthy, term‐pregnant obese women (Class II, BMI 35–40). Methods Systemic in vivo induction of eleven pro‐ and anti‐inflammatory biomarkers and acute phase proteins was assessed in plasma immediately prior to and again following Caesarian section surgery. Independently, innate immune capacity was examined by stimulating freshly isolated PBMC in vitro with a panel of defined PRR‐ligands for TLR4, TLR8, TLR3, and RLR 24 h post‐surgery. Results The kinetics and magnitude of the in vivo inflammatory responses examined were indistinguishable in the two populations across the broad range of biomarkers examined, despite the fact that obese women had higher baseline inflammatory status. Deliberate in vitro stimulation with a range of PRR ligands also elicited pro‐ and anti‐inflammatory cytokine responses that were indistinguishable between control and obese mothers. Conclusions Acute in vivo innate immune responses to C‐section, as well as subsequent in vitro stimulation with a panel of microbial mimics, are not detectably altered in Class II obese women. The data argue that while Class II obesity is undesirable, it has minimal impact on the in vivo inflammatory response, or innate immunomodulatory capacity, in women selecting C‐section. PMID:28544689

Osthole ameliorates neurogenic and inflammatory hyperalgesia by modulation of iNOS, COX-2, and inflammatory cytokines in mice.

PubMed

Singh, Gurjit; Bhatti, Rajbir; Mannan, Rahul; Singh, Drishtant; Kesavan, Anup; Singh, Palwinder

2018-05-07

Osthole is a bioactive component reported in medicinal plants such as Angelica pubescens and Cnidium monnieri, known for analgesic activity. However, the toxicity, median effective dose (ED 50 ), and dual modulation of nitric oxide and cyclooxygenase pathways along with inflammatory cytokines of osthole are yet to be determined. The animals (mice) were assessed for general behaviour and mortality in varying doses (50, 300, and 2000 mg kg -1 ) of osthole for acute toxicity over 14 days. The analgesic activity was investigated using acetic acid and formalin-induced hyperalgesia, and anti-inflammatory activity was explored in carrageenan-induced paw oedema. ED 50 of osthole was calculated using Design Expert software. Involvement of nitric oxide and cyclooxygenase pathways was investigated by agonist challenges with L-arginine and substance P, respectively. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined in spinal sections by immunohistochemical analysis. Lipopolysaccharide (LPS) challenge was used to assess in vivo effect on inflammatory cytokines (TNFα and IL-6). Acute toxicity studies revealed no behavioural abnormality or mortality on osthole treatment and unremarkable histological findings. Osthole was found to significantly decrease acetic acid and formalin-induced hyperalgesia (ED 50  = 5.43 mg kg -1 ) and carrageenan-induced paw oedema with no toxicity symptoms. Osthole produced a marked decrease in iNOS and COX-2 expression as well as TNFα and IL-6. The findings corroborate to modulation of iNOS and COX-2 and inflammatory cytokines by osthole. This study provides promising insights and prospects for application of osthole in pain management.

Transcranial direct current stimulation improves long-term memory deficits in an animal model of attention-deficit/hyperactivity disorder and modulates oxidative and inflammatory parameters.

PubMed

Leffa, Douglas Teixeira; Bellaver, Bruna; Salvi, Artur Alban; de Oliveira, Carla; Caumo, Wolnei; Grevet, Eugenio Horacio; Fregni, Felipe; Quincozes-Santos, André; Rohde, Luis Augusto; Torres, Iraci L S

2018-04-05

Transcranial direct current stimulation (tDCS) is a technique that modulates neuronal activity and has been proposed as a potential therapeutic tool for attention-deficit/hyperactivity disorder (ADHD) symptoms. Although pilot studies have shown evidence of efficacy, its mechanism of action remains unclear. We evaluated the effects of tDCS on behavioral (working and long-term memory) and neurochemical (oxidative and inflammatory parameters) outcomes related to ADHD pathophysiology. We used the most widely accepted animal model of ADHD: spontaneously hypertensive rats (SHR). The selected behavioral outcomes have been shown to be altered in both ADHD patients and animal models, and were chosen for their relation to the proposed mechanistic action of tDCS. Adult male SHR and their control, the Wistar Kyoto rats (WKY), were subjected to 20 min of bicephalic tDCS or sham stimulation for 8 consecutive days. Working memory, long-term memory, and neurochemical outcomes were evaluated. TDCS improved long-term memory deficits presented by the SHR. No change in working memory performance was observed. In the hippocampus, tDCS increased both the production of reactive oxygen species in SHR and the levels of the antioxidant molecule glutathione in both strains. TDCS also modulated inflammatory response in the brains of WKY by downregulating pro-inflammatory cytokines. TDCS had significant effects that were specific for strain, type of behavioral and neurochemical outcomes. The long-term memory improvement in the SHR may point to a possible therapeutic role of tDCS in ADHD that does not seem to be mediated by inflammatory markers. Additionally, the anti-inflammatory effects observed in the brain of WKY after tDCS needs to be further explored. Copyright © 2018 Elsevier Inc. 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.

Impact of nutrition on pollutant toxicity: an update with new insights into epigenetic regulation

PubMed Central

Hoffman, Jessie B; Petriello, Michael C; Hennig, Bernhard

2017-01-01

Exposure to environmental pollutants is a global health problem and is associated with the development of many chronic diseases including cardiovascular disease, diabetes, and metabolic syndrome. There is a growing body of evidence that nutrition can both positively and negatively modulate the toxic effects of pollutant exposure. Diets high in pro-inflammatory fats, such as linoleic acid, can exacerbate pollutant toxicity while diets rich in bioactive and anti-inflammatory food components, including omega-3 fatty acids and polyphenols, can attenuate toxicant-associated inflammation. Previously, researchers have elucidated direct mechanisms of nutritional modulation including alteration of NF-κB signaling, but recently increased focus has been given to the ways in which nutrition and pollutants affect epigenetics. Nutrition has been demonstrated to modulate epigenetic markers that have been linked either to increased disease risks or to protection against diseases. Overnutrition (i.e. obesity) and undernutrition (i.e. famine) have been observed to alter prenatal epigenetic tags that may increase the risk of offspring developing disease later in life. Conversely, bioactive food components, including curcumin, have been shown to alter epigenetic markers that suppress activation of NF-κB, thus reducing inflammatory responses. Exposure to pollutants also alters epigenetic markers and may contribute to inflammation and disease. It has been demonstrated that pollutants, via epigenetic modulations, can increase activation of NF-κB and upregulate miRNAs associated with inflammation, cardiac injury, and oxidative damage. Importantly, recent evidence suggests that nutritional components, including EGCG, can protect against pollutant-induced inflammation through epigenetic regulation of pro-inflammatory target genes of NF-κB. Further research is needed to better understand how nutrition can modulate pollutant toxicity through epigenetic regulation. Further research is needed to better understand how nutrition can modulate pollutant toxicity through epigenetic regulation. Therefore, the objective of this review is to elucidate the current evidence linking epigenetic changes to pollutant-induced diseases and how this regulation may be modulated by nutrients allowing for the development of future personalized lifestyle interventions. PMID:28076319

Vascular and Inflammatory Factors in the Pathophysiology of Blast-Induced Brain Injury

PubMed Central

Elder, Gregory A.; Gama Sosa, Miguel A.; De Gasperi, Rita; Stone, James Radford; Dickstein, Dara L.; Haghighi, Fatemeh; Hof, Patrick R.; Ahlers, Stephen T.

2015-01-01

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI. PMID:25852632

A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease.

PubMed

Alvarado, Raquel; O'Brien, Bronwyn; Tanaka, Akane; Dalton, John P; Donnelly, Sheila

2015-02-01

Parasitic worms (helminths) reside in their mammalian hosts for many years. This is attributable, in part, to their ability to skew the host's immune system away from pro-inflammatory responses and towards anti-inflammatory or regulatory responses. This immune modulatory ability ensures helminth longevity within the host, while simultaneously minimises tissue destruction for the host. The molecules that the parasite releases clearly exert potent immune-modulatory actions, which could be exploited clinically, for example in the prophylactic and therapeutic treatment of pro-inflammatory and autoimmune diseases. We have identified a novel family of immune-modulatory proteins, termed helminth defence molecules (HDMs), which are secreted by several medically important helminth parasites. These HDMs share biochemical and structural characteristics with mammalian cathelicidin-like host defence peptides (HDPs), which are significant components of the innate immune system. Like their mammalian counterparts, parasite HDMs block the activation of macrophages via toll like receptor (TLR) 4 signalling, however HDMs are significantly less cytotoxic than HDPs. HDMs can traverse the cell membrane of macrophages and enter the endolysosomal system where they reduce the acidification of lysosomal compartments by inhibiting vacuolar (v)-ATPase activity. In doing this, HDMs can modulate critical cellular functions, such as cytokine secretion and antigen processing/presentation. Here, we review the role of macrophages, specifically their lysosomal mediated activities, in the initiation and perpetuation of pro-inflammatory immune responses. We also discuss the potential of helminth defence molecules (HDMs) as therapeutics to counteract the pro-inflammatory responses underlying autoimmune disease. Given the current lack of effective, non-cytotoxic treatment options to limit the progression of autoimmune pathologies, HDMs open novel treatment avenues. Crown Copyright © 2014. Published by Elsevier GmbH. All rights reserved.

[Immunologic aspects of pathologic pain].

PubMed

Evseev, V A; Igon'kina, S I; Vetrilé, L A

2003-01-01

The scientific review is devoted to an analysis of neuro-immune aspects of the pathological pain and to the role of disregulation between the central nervous system (CNS) and the immune system in triggering the mechanisms of such pain. The importance of anti-inflammatory cytokines (interleukins, and tumor necrosis factor) as well as of autoantibodies to neuro-mediators in the pathogenesis of different forms of hyperalgetic conditions is evaluated. New data are discussed, which are related with the possibility of modulating the antibodies to neuro-transmitters (serotonin and catecholamines) of experimental neuropathic pain syndromes.

Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IκBα.

PubMed

Bao, Yan; Wu, Xuewei; Chen, Jinjing; Hu, Xiangming; Zeng, Fuxing; Cheng, Jianjun; Jin, Hong; Lin, Xin; Chen, Lin-Feng

2017-05-16

Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 ( Mknk2 ). Brd4 -deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases.

PubMed

Frey, Benjamin; Hehlgans, Stephanie; Rödel, Franz; Gaipl, Udo S

2015-11-28

Inflammation is a homeostatic mechanism aiming to maintain tissue integrity. The underlying immunological mechanisms and the interrelationship between ionizing radiation and inflammation are complex and multifactorial on cellular and chemical levels. On the one hand, radiation with single doses exceeding 1 Gy might initiate inflammatory reactions and thereby impact on tumor development. On the other hand, radiation is capable of attenuating an established inflammatory process, which is clinically used for the treatment of inflammatory and degenerative diseases with low-dose radiotherapy (single dose <1 Gy). At higher doses, ionizing radiation, especially in combination with additional immune stimulation, fosters the induction of immunogenic forms of tumor cell death and shifts the tumor microenvironment as well as the infiltration of immune cells from an anti- to a pro-inflammatory state. Distinct tumor infiltrating immune cells predict the response to radiochemotherapy in a multitude of tumor entities. While a high tumor infiltration of these adaptive immune cells mostly predicts a favorable disease outcome, a high infiltration of tumor-associated macrophages predicts an unfavorable response. Pro-inflammatory events should dominate over anti-inflammatory ones in this scenario. This review focuses on how ionizing radiation modulates inflammatory events in benign inflammatory and in malign diseases. A special focus is set on the role of tumor infiltrating lymphocytes and macrophages as biomarkers to predict treatment response and anti-tumor immunity and on mechanisms implicated in the anti-inflammatory effects of low-dose radiation therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology: Applications for Drug Repurposing

PubMed Central

de Anda-Jáuregui, Guillermo; Guo, Kai; McGregor, Brett A.; Hur, Junguk

2018-01-01

The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space. PMID:29545755

Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology: Applications for Drug Repurposing.

PubMed

de Anda-Jáuregui, Guillermo; Guo, Kai; McGregor, Brett A; Hur, Junguk

2018-01-01

The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space.

Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System.

PubMed

Withers, David R; Hepworth, Matthew R

2017-01-01

The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3) are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of "exogenous" signals, such as dietary metabolites and commensal microbes, and "endogenous" host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a "communications hub" in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell-cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases.

Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System

PubMed Central

Withers, David R.; Hepworth, Matthew R.

2017-01-01

The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3) are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of “exogenous” signals, such as dietary metabolites and commensal microbes, and “endogenous” host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a “communications hub” in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell–cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases. PMID:29085366

Comparison of the interleukin-1β-inducing potency of allergenic spores from higher fungi (Basidiomycetes) in a cryopreserved human whole blood system

PubMed Central

Rivera-Mariani, Félix E.; Vysyaraju, Kranthi; Negherbon, Jesse; Levetin, Estelle; Horner, W. Elliot; Hartung, Thomas; Breysse, Patrick N.

2014-01-01

Background Spores from basidiomycete fungi (basidiospores) are highly prevalent in the atmosphere of urban and rural settings. Studies have confirmed their potential to affect human health as allergens. Less is known about their potential to serve as stimuli of the innate immune system and induce pro-inflammatory reactions. Methods In this study, we evaluated the pro-inflammatory potential of spores from 11 allergenic gilled (Pleurotus ostreatus, Oudemansiella radicata, Armillaria tabescens, Coprinus micaceus, Pluteus cervinus, Chlorophyllum molybdites) and non-gilled (Pisolithus arhizus, Merulius tremullosus, Calvatia cyathiformis, Lycoperdon pyriforme, Boletus bicolor) basidiomycetes fungi based on their potency to induce the release of the pro-inflammatory cytokine interleukin (IL)-1β in a cryopreserved human whole blood system. In addition, the role of morphological features of the spores (surface area, shape, and pigmentation) were examined for their role in the spores’ interleukin (IL)-1β-including potency. Peripheral blood from healthy volunteers was collected, pooled, and cryopreserved. After stimulating the cryopreserved pooled blood with 106 to 103 basidiospores/ml, the concentration of IL-1β in culture supernatants was determined with ELISA. Results Basidiospores manifested concentration-dependent IL-1β-inducing potency, which was more noteworthy among basidiospores from gilled basidiomycetes. At higher concentrations of basidiospores, the IL-1β-inducing potency was able to be differentiated in the cryopreserved human whole blood system. Morphological features did not correlate with the IL-1β-inducing potency of the basidiospores, suggesting that non-morphological properties modulate the IL-1β-inducing potency. Conclusion Our data provides evidence of the pro-inflammatory potential of basidiospores, and the utility of cryopreserved human whole blood as a human-based in-vitro system to study the immune reactivity of allergenic basidiospores. PMID:24356469

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis.

PubMed

Bello, Ramatu Omenesa; Chin, Voon Kin; Abd Rachman Isnadi, Mohammad Faruq; Abd Majid, Roslaini; Atmadini Abdullah, Maizaton; Lee, Tze Yan; Amiruddin Zakaria, Zainul; Hussain, Mohd Khairi; Basir, Rusliza

2018-04-11

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

[Antioxidant and anti-inflammatory modulation of exercise during aging].

PubMed

Galle, Fernando Alexis; Martella, Diana; Bresciani, Guilherme

2018-06-10

Aging is characterised by a gradual loss of the functional reserve. This, along with the fostering of sedentary habits and the increase in risk factors, causes a deterioration of antioxidant defences and an increase of the circulatory levels of inflammatory and oxidative markers, boosting a low-rate chronic inflammation, defined as inflamm-aging. This phenomenon is present in the aetiopathology of chronic diseases, as well as in cognitive deterioration cases associated with aging. The objective of this review is to describe the modulation of antioxidant and anti-inflammatory effects of physical exercise of moderate intensity and volume in the elderly. Evidence of its effectiveness as a non-pharmacological resource is presented, which decreases some deleterious effects of aging. This is mainly due to its neuroprotective action, the increase in circulating anti-inflammatory markers, and the improvement of antioxidant defence derived from its practice. Copyright © 2018 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Proteomic Analysis Reveals Inflammation Modulation of κ/ι-Carrageenan Hexaoses in Lipopolysaccharide-Induced RAW264.7 Macrophages.

PubMed

Guo, Juanjuan; Chen, Jinghao; Lu, Xu; Guo, Zebin; Huang, Zhiwei; Zeng, Shaoxiao; Zhang, Yi; Zheng, Baodong

2018-05-09

κ/ι-Carrageenan hexaoses (κ/ι-neocarrahexaoses, KCO-4) are a type of carrageenan oligosaccharide that have a broad spectrum of bioactivities due to the presence of sulfate groups. However, the anti-inflammatory capacity of purified carrageenan oligosaccharides and the underlying mechanism has not been completely elucidated. The present study aimed to investigate inflammatory signaling modulation of KCO-4 in LPS-induced macrophages using a quantitative proteomic strategy. KCO-4 inhibited the oversecretion of inflammatory mediators (i.e., NO, TNF-α, IL-1β, IL-8, iNOS, and COX-2). KCO-4 treatment altered proteome profile, and metabolic processes in mitochondria were significantly disrupted. The IPA network analysis proposed that KCO-4 triggered the NF-κB signaling pathway-dependent anti-inflammation process through the inhibition of CD14/Rel@p50 in LPS-induced RAW264.7 macrophages. These data improve our understanding of the anti-inflammatory mechanism and contribute to exposure biomarker screening of κ-carrageenan oligosaccharides.

Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin.

PubMed

Shao, Ping; Ma, Linxiao; Ren, Yile; Liu, Huijie

2017-10-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is associated with symptoms, including synovial membrane inflammatory pain, joint synovitis and stiffness. However, there are no effective methods available to cure this disease. In the present study, rapamycin was used to modulate immunity in RA. To limit the cytotoxicity of rapamycin, rapamycin was loaded into well‑characterized biocompatible nanoparticles. In vitro, rapamycin particles downregulated the activation of dendritic cell surface markers, including CD80+ and CD40+, upon interacting with macrophages. The rapamycin particles reduced the secretion of inflammatory cytokines, including interleukin (IL)‑6, tumor necrosis factor (TNF) and IL‑1β, which are characteristic of RA. In vivo, the rapamycin particles decreased the symptoms of RA in mice, and the production of inflammatory cytokines was associated with the occurrence of RA. The present study partially revealed the interactions between rapamycin and two types of immune cell in RA disease, and may potentially offer a solution to improve the treatment of RA.

Differential effects of sertraline in a predator exposure animal model of post-traumatic stress disorder.

PubMed

Wilson, C Brad; McLaughlin, Leslie D; Ebenezer, Philip J; Nair, Anand R; Dange, Rahul; Harre, Joseph G; Shaak, Thomas L; Diamond, David M; Francis, Joseph

2014-01-01

Serotonin (5-HT), norepinephrine (NE), and other neurotransmitters are modulated in post-traumatic stress disorder (PTSD). In addition, pro-inflammatory cytokines (PIC) are elevated during the progression of the disorder. Currently, the only approved pharmacologic treatments for PTSD are the selective-serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, but their efficacy in treating PTSD is marginal at best. In combat-related PTSD, SSRIs are of limited effectiveness. Thus, this study sought to analyze the effects of the SSRI sertraline on inflammation and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. We hypothesized that sertraline would diminish inflammatory components and increase 5-HT but might also affect levels of other neurotransmitters, particularly NE. PTSD-like effects were induced in male Sprague-Dawley rats (n = 6/group × 4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1 h on days 1 and 11 of a 31-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, treatment group animals were injected intraperitoneally (i.p.) with sertraline HCl at 10 mg/kg for 7 consecutive days, while controls received i.p. vehicle. The animals were subsequently sacrificed on day 8. Sertraline attenuated inflammatory markers and normalized 5-HT levels in the central nervous system (CNS). In contrast, sertraline produced elevations in NE in the CNS and systemic circulation of SSRI treated PTSD and control groups. This increase in NE suggests SSRIs produce a heightened noradrenergic response, which might elevate anxiety in a clinical setting.

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

Low-dose naltrexone for disease prevention and quality of life.

PubMed

Brown, Norman; Panksepp, Jaak

2009-03-01

The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise, social bonding, and emotional well-being, as well as amelioration of psychiatric problems such a autism and depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily and mental ailments through its ability to beneficially modulate both the immune system and the brain neurochemistries that regulate positive affect.

[Oxygen and the superoxide anion. Modulation of NADPH oxidase?].

PubMed

Delbosc, S; Cristol, J P; Descomps, B; Chénard, J; Sirois, P

2001-01-01

Oxidative stress which results from an imbalance between oxidant production and antioxidant defense mechanisms can promote modifications of lipids, proteins and nucleic acids. This review focuses on the different pathways leading to Reactive Oxygen Species (ROS) production in particular on NADPH oxidase activation. This enzyme is localized in numerous cells including phagocytes and vascular cells and composed of membrane and cytosolic sub-units. The activation of the NADPH oxidase is largely involved in inflammation associated diseases such as asthma, Systemic Inflammatory Response Syndrome and aging associated diseases such as atherosclerosis and neurodeneratives diseases. The modulation of NADPH oxidase could be a way to limit or prevent the development of these diseases.

Extracorporeal photopheresis: Review of technical aspects.

PubMed

Arora, Satyam; Setia, Rasika

2017-01-01

Extracorporeal photochemotherapy (ECP) is considered as an immune modulating therapy majorly targeting the T cells of the Immune system. ECP induces an anti-inflammatory condition with tolerogenic responses without inducing a global immunosuppression state which is a typical feature of other therapeutic options such as steroids. Clinical indication of ECP has grown over time since its initial applications. Our review discusses the technical aspects of the concept of photopheresis with the available methods for its clinical applications.

Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

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

Xu, Shanqin; Zhi, Hui; Hou, Xiuyun

2011-07-08

Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. Inmore » cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells through influencing ERK-NF-{kappa}B crosstalk, which may contribute to angiotensin II-induced inflammatory disorders related to cardiovascular diseases.« less

Treating Gulf War Illness with Novel Anti-Inflammatories: A Screening of Botantical Microglia Modulators

DTIC Science & Technology

2015-10-01

SUBJECT TERMS Gulf War Illness, botanical , anti-inflammatory, biomarker, microglia, improvement, treatment 16. SECURITY CLASSIFICATION OF: 17...promising botanical anti-inflammatories for the treatment of Gulf War Illness (GWI). A second, exploratory, aim is to identify biomarkers of GWI...3 different botanical compounds and placebo over a 300 day period. Each participant will also participate in a 30-day baseline period starting the

Effects of low-intensity ultrahigh frequency electromagnetic radiation on inflammatory processes.

PubMed

Lushnikov, K V; Shumilina, Yu V; Yakushina, V S; Gapeev, A B; Sadovnikov, V B; Chemeris, N K

2004-04-01

Low-intensity ultrahigh frequency electromagnetic radiation (42 GHz, 100 microW/cm(2)) reduces the severity of inflammation and inhibits production of active oxygen forms by inflammatory exudate neutrophils only in mice with inflammatory process. These data suggest that some therapeutic effects of electromagnetic radiation can be explained by its antiinflammatory effect which is realized via modulation of functional activity of neutrophils in the focus of inflammation.

Induction of Mincle by Helicobacter pylori and consequent anti-inflammatory signaling denote a bacterial survival strategy

PubMed Central

Devi, Savita; Rajakumara, Eerappa; Ahmed, Niyaz

2015-01-01

Evasion of innate immune recognition is one of the key strategies for persistence of Helicobacter pylori, by virtue of its ability to modulate or escape the host innate immune receptors and signaling pathways. C-type lectin receptors (CLRs) predominantly expressed by macrophages are pivotal in tailoring immune response against pathogens. The recognition of glyco or carbohydrate moieties by Mincle (Macrophage inducible C-type lectin) is emerging as a crucial element in anti-fungal and anti-mycobacterial immunity. Herein, we demonstrate the role of Mincle in modulation of innate immune response against H. pylori infection. Our results revealed an upregulated expression of Mincle which was independent of direct host cell contact. Upon computational modelling, Mincle was observed to interact with the Lewis antigens of H. pylori LPS and possibly activating an anti-inflammatory cytokine production, thereby maintaining a balance between pro- and anti-inflammatory cytokine production. Furthermore, siRNA mediated knockdown of Mincle in human macrophages resulted in up regulation of pro-inflammatory cytokines and consequent down regulation of anti-inflammatory cytokines. Collectively, our study demonstrates a novel mechanism employed by H. pylori to escape clearance by exploiting functional plasticity of Mincle to strike a balance between pro-and anti-inflammatory responses ensuring its persistence in the host. PMID:26456705

Immune-modulating effects in mouse dendritic cells of lactobacilli and bifidobacteria isolated from individuals following omnivorous, vegetarian and vegan diets.

PubMed

Luongo, Diomira; Treppiccione, Lucia; Sorrentino, Alida; Ferrocino, Ilario; Turroni, Silvia; Gatti, Monica; Di Cagno, Raffaella; Sanz, Yolanda; Rossi, Mauro

2017-09-01

Lactobacilli and bifidobacteria play a primary role in modulation of gut immunity. By considering that microbiota composition depends on various factors, including diet, we asked whether functional differences could characterize faecal populations of lactobacilli and bifidobacteria isolated from individuals with different dietary habits. 155 healthy volunteers who followed omnivorous, ovo-lacto-vegetarian or vegan diets were recruited at four Italian centres (Turin, Parma, Bologna and Bari). Faecal samples were collected; lactobacilli and bifidobacteria were isolated on selective media and their immunomodulatory activity was tested in mouse dendritic cells (DCs). Pre-incubation with lactobacilli increased LPS-induced expression of the maturation markers CD80 and CD86, whereas pre-incubation with bifidobacteria decreased such expression. Analysis of the cytokine profile indicated that strains of both genera induced down-regulation of IL-12 and up-regulation of IL-10, whereas expression of TNF-α was not modulated. Notably, analysis of anti-inflammatory potential (IL-10/IL-12 ratio) showed that lactobacilli evoked a greater anti-inflammatory effect than did bifidobacteria in the omnivorous group (P<0.05). We also found significantly reduced anti-inflammatory potential in the bacterial strains isolated from Bari's volunteers in comparison with those from the cognate groups from the other centres. In conclusion, lactobacilli and bifidobacteria showed a genus-specific ability of modulating in vitro innate immunity associated with a specific dietary habit. Furthermore, the geographical area had a significant impact on the anti-inflammatory potential of some components of faecal microbiota. Copyright © 2017 Elsevier Ltd. All rights reserved.

Review article: the gut microbiome in inflammatory bowel disease-avenues for microbial management.

PubMed

McIlroy, J; Ianiro, G; Mukhopadhya, I; Hansen, R; Hold, G L

2018-01-01

The concept of an altered collective gut microbiota rather than identification of a single culprit is possibly the most significant development in inflammatory bowel disease research. We have entered the "omics" era, which now allows us to undertake large-scale/high-throughput microbiota analysis which may well define how we approach diagnosis and treatment of inflammatory bowel disease (IBD) in the future, with a strong steer towards personalised therapeutics. To assess current epidemiological, experimental and clinical evidence of the current status of knowledge relating to the gut microbiome, and its role in IBD, with emphasis on reviewing the evidence relating to microbial therapeutics and future microbiome modulating therapeutics. A Medline search including items 'intestinal microbiota/microbiome', 'inflammatory bowel disease', 'ulcerative colitis', 'Crohn's disease', 'faecal microbial transplantation', 'dietary manipulation' was performed. Disease remission and relapse are associated with microbial changes in both mucosal and luminal samples. In particular, a loss of species richness in Crohn's disease has been widely observed. Existing therapeutic approaches broadly fall into 3 categories, namely: accession, reduction or indirect modulation of the microbiome. In terms of microbial therapeutics, faecal microbial transplantation appears to hold the most promise; however, differences in study design/methodology mean it is currently challenging to elegantly translate results into clinical practice. Existing approaches to modulate the gut microbiome are relatively unrefined. Looking forward, the future of microbiome-modulating therapeutics looks bright with several novel strategies/technologies on the horizon. Taken collectively, it is clear that ignoring the microbiome in IBD is not an option. © 2017 John Wiley & Sons Ltd.

Tributyltin exposure alters cytokine levels in mouse serum.

PubMed

Lawrence, Shanieek; Pellom, Samuel T; Shanker, Anil; Whalen, Margaret M

2016-11-01

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution.

PubMed

Skaper, Stephen D; Facci, Laura; Barbierato, Massimo; Zusso, Morena; Bruschetta, Giuseppe; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Giusti, Pietro

2015-10-01

Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell-mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naïve PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self-defense against inflammation.

Intra-articular administration of xenogeneic neonatal Mesenchymal Stromal Cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis.

PubMed

Saulnier, N; Viguier, E; Perrier-Groult, E; Chenu, C; Pillet, E; Roger, T; Maddens, S; Boulocher, C

2015-01-01

The anti-inflammatory and anti-catabolic effects of neonatal Mesenchymal Stromal Cell (MSC) were investigated in a xenogeneic model of mild osteoarthritis (OA). The paracrine properties of MSC on synoviocytes were further investigated in vitro. OA was induced by medial meniscal release (MMR) in 30 rabbit knees. A single early (day 3) or delayed (day 15) intra-articular (IA) injection of MSC isolated from equine Umbilical Cord Wharton's jelly (UC-MSC) was performed. Rabbits were euthanized on days 15 or 56. OA grading was performed and gene expression of inflammatory cytokines and metalloproteinases was measured in synovial tissue. Paracrine effects of UC-MSC were investigated using UC-conditioned vs control medium on rabbit primary synoviocytes stimulated with interleukin 1 beta in vitro. No adverse local or systemic responses were observed clinically after xenogeneic UC-MSC injection. At study end point, cartilage fibrillation was lower in early treatment than in delayed treatment group. Cellular infiltrate was observed in the synovium of both UC-MSC groups. OA synovium exhibited a reduced expression of metalloproteinases-1, -3, -13 in the early cell-treated group at d56. In vitro, UC-conditioned medium exerted anti-inflammatory and anti-catabolic effects on synoviocytes exposed to pro-inflammatory stimulus. Early IA injection of equine UC-MSC was effective in preventing OA signs in rabbit knees following MMR. UC-MSC target the synovium and modulate the gene expression pattern of synoviocytes to promote an anti-catabolic environment. This confirms the synovium is a major target and mediator of MSC therapy, modulating the expression of matrix-degrading enzymes. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells.

PubMed

Cribbs, Adam; Hookway, Edward S; Wells, Graham; Lindow, Morten; Obad, Susanna; Oerum, Henrik; Prinjha, Rab K; Athanasou, Nick; Sowman, Aneka; Philpott, Martin; Penn, Henry; Soderstrom, Kalle; Feldmann, Marc; Oppermann, Udo

2018-02-16

Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain-containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

The use of Brazilian propolis for discovery and development of novel anti-inflammatory drugs.

PubMed

Franchin, Marcelo; Freires, Irlan Almeida; Lazarini, Josy Goldoni; Nani, Bruno Dias; da Cunha, Marcos Guilherme; Colón, David Fernando; de Alencar, Severino Matias; Rosalen, Pedro Luiz

2018-06-10

Anti-Inflammatory drugs have been routinely used in the management of acute and chronic inflammatory conditions. Nevertheless, their undesirable side and adverse effects have encouraged the development of more selective, tolerable and efficacious drugs able to modulate the inflammatory process through distinct mechanisms than those of drugs currently available in the market, for instance, inhibition of leukocyte recruitment (chemotaxis, rolling, adhesion and transmigration). Natural products, including Brazilian propolis, have been considered a rich source of anti-inflammatory molecules due to a very complex phytochemical diversity. Brazil has at least thirteen distinct types of propolis and many bioactive compounds have been isolated therefrom, such as apigenin, artepillin C, vestitol, neovestitol, among others. These molecules were proven to play a significant immunomodulatory role through (i) inhibition of inflammatory cytokines (e.g. TNF-α) and chemokines (CXCL1/KC and CXCL2/MIP2); (ii) inhibition of IκBα, ERK1/2, JNK and p38MAPK phosphorylation; (iii) inhibition of NF-κB activation; and (iv) inhibition of neutrophil adhesion and transmigration (ICAM-1, VCAM-1 and E-selectin expression). In this review, we shed light on the new advances in the research of compounds isolated from Brazilian propolis from Apis mellifera bees as potentially novel anti-inflammatory drugs. The compilation of data and insights presented herein may open further avenues for the pharmacological management of oral and systemic inflammatory conditions. Further research should focus on clinical and acute/chronic toxicological validation of the most promising compounds described in this review. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

PubMed Central

Prabhu, Sumanth D.; Frangogiannis, Nikolaos G.

2016-01-01

In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure. PMID:27340270

Inhibitory effects of bee venom on mast cell-mediated allergic inflammatory responses.

PubMed

Kang, Yun-Mi; Chung, Kyung-Sook; Kook, In-Hoon; Kook, Yoon-Bum; Bae, Hyunsu; Lee, Minho; An, Hyo-Jin

2018-06-01

Although bee venom (BV) is a toxin that causes bee stings to be painful, it has been widely used clinically for the treatment of certain immune‑associated diseases. BV has been used traditionally for the treatment of chronic inflammatory diseases. In this regard, the present study analyzed the effect of BV on the regulation of inflammatory mediator production by mast cells and their allergic inflammatory responses in an animal model. HMC‑1 cells were treated with BV prior to stimulation with phorbol‑12‑myristate 13‑acetate plus calcium ionophore A23187 (PMACI). The production of allergy‑associated pro‑inflammatory mediators was examined, and the underlying mechanisms were investigated. Furthermore, to investigate whether BV exhibits anti‑inflammatory effects associated with anti‑allergic effects in vivo, a compound 48/80‑induced anaphylaxis model was used. BV inhibited histamine release, mRNA expression and production of cytokines in the PMACI‑stimulated HMC‑1 cells. Furthermore, the inhibitory effects of BV on mitogen‑activated protein kinase (MAPK), MAPK kinase, signal transducer and activator of transcription 3 (STAT3) and Akt were demonstrated. The present study also investigated the ability of BV to inhibit compound 48/80‑induced systemic anaphylaxis in vivo. BV protected the mice against compound 48/80‑induced anaphylactic‑associated mortality. Furthermore, BV suppressed the mRNA expression levels of pro‑inflammatory cytokines, and suppressed the activation of MAPK and STAT3 in this model. These results provide novel insights into the possible role of BV as a modulator for mast cell‑mediated allergic inflammatory disorders.

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

PubMed Central

Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

2015-01-01

The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

c-Rel is Essential for the Development of Innate and T cell-Induced Colitis1

PubMed Central

Wang, Yanyan; Rickman, Barry H.; Poutahidis, Theofilos; Schlieper, Katherine; Jackson, Erin A.; Erdman, Susan E.; Fox, James G.; Horwitz, Bruce H.

2008-01-01

Inflammatory bowel disease is a chronic inflammatory response of the gastrointestinal tract mediated in part by an aberrant response to intestinal microflora. Expression of IL-23 subunits p40 and p19 within cells of the innate immune system plays a central role in the development of lower bowel inflammation in response inflammatory challenge. The NF-κB subunit c-Rel can regulate expression of IL-12/23 subunits suggesting that it could have a critical role in mediating the development of chronic inflammation within the lower bowel. Here we have analyzed the role of c-Rel within the innate immune system in the development of lower bowel inflammation, in two well-studied models of murine colitis. We have found that the absence of c-Rel significantly impaired the ability of H. hepaticus to induce colitis upon infection of RAG-2-deficient mice, and ameliorated the ability of CD4+CD45RBhigh T cells to induce disease upon adoptive transfer into RAG-deficient mice. The absence of c-Rel interfered with the expression of IL-12/23 subunits both in cultured primary macrophages and within the colon. Thus, c-Rel plays a critical role in regulating the innate inflammatory response to microflora within the lower bowel, likely through its ability to modulate expression of IL-12/23 family members. PMID:18523276

Diet and microbiota in inflammatory bowel disease: The gut in disharmony.

PubMed

Rapozo, Davy C M; Bernardazzi, Claudio; de Souza, Heitor Siffert Pereira

2017-03-28

Bacterial colonization of the gut shapes both the local and the systemic immune response and is implicated in the modulation of immunity in both healthy and disease states. Recently, quantitative and qualitative changes in the composition of the gut microbiota have been detected in Crohn's disease and ulcerative colitis, reinforcing the hypothesis of dysbiosis as a relevant mechanism underlying inflammatory bowel disease (IBD) pathogenesis. Humans and microbes have co-existed and co-evolved for a long time in a mutually beneficial symbiotic association essential for maintaining homeostasis. However, the microbiome is dynamic, changing with age and in response to environmental modifications. Among such environmental factors, food and alimentary habits, progressively altered in modern societies, appear to be critical modulators of the microbiota, contributing to or co-participating in dysbiosis. In addition, food constituents such as micronutrients are important regulators of mucosal immunity, with direct or indirect effects on the gut microbiota. Moreover, food constituents have recently been shown to modulate epigenetic mechanisms, which can result in increased risk for the development and progression of IBD. Therefore, it is likely that a better understanding of the role of different food components in intestinal homeostasis and the resident microbiota will be essential for unravelling the complex molecular basis of the epigenetic, genetic and environment interactions underlying IBD pathogenesis as well as for offering dietary interventions with minimal side effects.

Diet and microbiota in inflammatory bowel disease: The gut in disharmony

PubMed Central

Rapozo, Davy C M; Bernardazzi, Claudio; de Souza, Heitor Siffert Pereira

2017-01-01

Bacterial colonization of the gut shapes both the local and the systemic immune response and is implicated in the modulation of immunity in both healthy and disease states. Recently, quantitative and qualitative changes in the composition of the gut microbiota have been detected in Crohn’s disease and ulcerative colitis, reinforcing the hypothesis of dysbiosis as a relevant mechanism underlying inflammatory bowel disease (IBD) pathogenesis. Humans and microbes have co-existed and co-evolved for a long time in a mutually beneficial symbiotic association essential for maintaining homeostasis. However, the microbiome is dynamic, changing with age and in response to environmental modifications. Among such environmental factors, food and alimentary habits, progressively altered in modern societies, appear to be critical modulators of the microbiota, contributing to or co-participating in dysbiosis. In addition, food constituents such as micronutrients are important regulators of mucosal immunity, with direct or indirect effects on the gut microbiota. Moreover, food constituents have recently been shown to modulate epigenetic mechanisms, which can result in increased risk for the development and progression of IBD. Therefore, it is likely that a better understanding of the role of different food components in intestinal homeostasis and the resident microbiota will be essential for unravelling the complex molecular basis of the epigenetic, genetic and environment interactions underlying IBD pathogenesis as well as for offering dietary interventions with minimal side effects. PMID:28405140

Anti-Inflammatory and Anti-Obesity Properties of Food Bioactive Components: Effects on Adipose Tissue

PubMed Central

Jayarathne, Shasika; Koboziev, Iurii; Park, Oak-Hee; Oldewage-Theron, Wilna; Shen, Chwan-Li; Moustaid-Moussa, Naima

2017-01-01

Obesity is an epidemic and costly disease affecting 13% of the adult population worldwide. Obesity is associated with adipose tissue hypertrophy and hyperplasia, as well as pathologic endocrine alterations of adipose tissue including local and chronic systemic low-grade inflammation. Moreover, this inflammation is a risk factor for both metabolic syndrome (MetS) and insulin resistance. Basic and clinical studies demonstrate that foods containing bioactive compounds are capable of preventing both obesity and adipose tissue inflammation, improving obesity-associated MetS in human subjects and animal models of obesity. In this review, we discuss the anti-obesity and anti-inflammatory protective effects of some bioactive polyphenols of plant origin and omega-3 polyunsaturated fatty acids, available for the customers worldwide from commonly used foods and/or as components of commercial food supplements. We review how these bioactive compounds modulate cell signaling including through the nuclear factor-κB, adenosine monophosphate-activated protein kinase, mitogen-activated protein kinase, toll-like receptors, and G-protein coupled receptor 120 intracellular signaling pathways and improve the balance of pro- and anti-inflammatory mediators secreted by adipose tissue and subsequently lower systemic inflammation and risk for metabolic diseases. PMID:29333376

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients.

PubMed

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D'Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-11-30

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

PubMed Central

Di Bari, Maria; Reale, Marcella; Di Nicola, Marta; Orlando, Viviana; Galizia, Sabrina; Porfilio, Italo; Costantini, Erica; D’Angelo, Chiara; Ruggieri, Serena; Biagioni, Stefano; Gasperini, Claudio; Tata, Ada Maria

2016-01-01

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. PMID:27916909

Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention.

PubMed

Mastellos, D C; Ricklin, D; Hajishengallis, E; Hajishengallis, G; Lambris, J D

2016-02-01

There is increasing appreciation that complement dysregulation lies at the heart of numerous immune-mediated and inflammatory disorders. Complement inhibitors are therefore being evaluated as new therapeutic options in various clinical translation programs and the first clinically approved complement-targeted drugs have profoundly impacted the management of certain complement-mediated diseases. Among the many members of the intricate protein network of complement, the central component C3 represents a 'hot-spot' for complement-targeted therapeutic intervention. C3 modulates both innate and adaptive immune responses and is linked to diverse immunomodulatory systems and biological processes that affect human pathophysiology. Compelling evidence from preclinical disease models has shown that C3 interception may offer multiple benefits over existing therapies or even reveal novel therapeutic avenues in disorders that are not commonly regarded as complement-driven, such as periodontal disease. Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience

PubMed Central

Ménard, Caroline; Pfau, Madeline L; Hodes, Georgia E; Russo, Scott J

2017-01-01

Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30–50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation, and hypothalamic-pituitary-adrenal axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to the current antidepressant treatments. PMID:27291462

Curcumin: A natural modulator of immune cells in systemic lupus erythematosus.

PubMed

Momtazi-Borojeni, Amir Abbas; Haftcheshmeh, Saeed Mohammadian; Esmaeili, Seyed-Alireza; Johnston, Thomas P; Abdollahi, Elham; Sahebkar, Amirhossein

2018-02-01

Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

High-intensity interval training improves inflammatory and adipokine profiles in postmenopausal women with metabolic syndrome.

PubMed

Steckling, Flávia Mariel; Farinha, Juliano Boufleur; Figueiredo, Felipe da Cunha; Santos, Daniela Lopes Dos; Bresciani, Guilherme; Kretzmann, Nélson Alexandre; Stefanello, Sílvio Terra; Courtes, Aline Alves; Beck, Maristela de Oliveira; Sangoi Cardoso, Manuela; Duarte, Marta Maria Medeiros Frescura; Moresco, Rafael Noal; Soares, Félix Alexandre Antunes

2018-02-12

This study investigate the effects of high-intensity interval training (HIIT) on systemic levels of inflammatory and hormonal markers in postmenopausal women with metabolic syndrome (MS). Fifteen postmenopausal women with MS completed the training on treadmills. Functional, body composition parameters, maximal oxygen uptake (VO 2 max), and lipid profile were assessed before and after HIIT. Serum or plasma levels of cytokines and hormonal markers were measured along the intervention. The analysis of messenger RNA (mRNA) expression of these cytokines was performed in peripheral blood mononuclear cells (PBMC). VO 2 max and some anthropometric parameters were improved after HIIT, while decreased levels of proinflammatory markers and increased levels of interleukin-10 (IL-10) were also found. Adipokines were also modulated after 12 weeks or training. The mRNA expression of the studied genes was unchanged after HIIT. In conclusion, HIIT benefits inflammatory and hormonal axis on serum or plasma samples, without changes on PBMC of postmenopausal MS patients.

Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis.

PubMed

Rook, Graham A W

2009-01-01

Man has moved rapidly from the hunter-gatherer environment to the living conditions of the rich industrialized countries. The hygiene hypothesis suggests that the resulting changed and reduced pattern of exposure to microorganisms has led to disordered regulation of the immune system, and hence to increases in certain inflammatory disorders. The concept began with the allergic disorders, but there are now good reasons for extending it to autoimmunity, inflammatory bowel disease, neuroinflammatory disorders, atherosclerosis, depression associated with raised inflammatory cytokines, and some cancers. This review discusses these possibilities in the context of Darwinian medicine, which uses knowledge of evolution to cast light on human diseases. The Darwinian approach enables one to correctly identify some of the organisms that are important for the 'Hygiene' or 'Old Friends' hypothesis, and to point to the potential exploitation of these organisms or their components in novel types of prophylaxis with applications in several branches of medicine.

Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

PubMed Central

Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

2011-01-01

Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

PubMed

Zaiss, Mario M; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D; Macpherson, Andrew J; Croese, John; Giacomin, Paul R; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J; Harris, Nicola L

2015-11-17

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Of worms, mice and man: an overview of experimental and clinical helminth-based therapy for inflammatory bowel disease.

PubMed

Heylen, Marthe; Ruyssers, Nathalie E; Gielis, Els M; Vanhomwegen, Els; Pelckmans, Paul A; Moreels, Tom G; De Man, Joris G; De Winter, Benedicte Y

2014-08-01

The incidence of inflammatory and autoimmune disorders is highest in well-developed countries which is directly related to their higher hygienic standards: it is suggested that the lack of exposure to helminths contributes to the susceptibility for immune-related diseases. Epidemiological, experimental and clinical data support the idea that helminths provide protection against immune-mediated diseases such as inflammatory bowel disease (IBD). The most likely mechanism for the suppression of immune responses by helminths is the release of helminth-derived immunomodulatory molecules. This article reviews the experimental and clinical studies investigating the therapeutic potential of helminth-based therapy in IBD and also focuses on the current knowledge of its immunomodulatory mechanisms of action highlighting innate as well as adaptive immune mechanisms. Identifying the mechanisms by which these helminths and helminth-derived molecules modulate the immune system will help in creating novel drugs for the treatment of IBD and other disorders that result from an overactive immune response. Copyright © 2014 Elsevier Inc. All rights reserved.

CCL5-Glutamate Cross-Talk in Astrocyte-Neuron Communication in Multiple Sclerosis.

PubMed

Pittaluga, Anna

2017-01-01

The immune system (IS) and the central nervous system (CNS) are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5) and the principal neurotransmitter in CNS (i.e., glutamate) in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS), but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.

Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

PubMed

Kim, Myung-Sunny; Yamamoto, Yasuhiko; Kim, Kyungjin; Kamei, Nozomu; Shimada, Takeshi; Liu, Libin; Moore, Kristin; Woo, Ju Rang; Shoelson, Steven E; Lee, Jongsoon

2013-01-01

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

PubMed Central

Carniglia, Lila; Durand, Daniela; Caruso, Carla; Lasaga, Mercedes

2013-01-01

Brain inflammation plays a central role in numerous brain pathologies. Microglia and astrocytes are the main effector cells that become activated when an inflammatory process takes place within the central nervous system. α-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with proven anti-inflammatory properties. It binds with highest affinity to the melanocortin receptor 4 (MC4R), which is present in astrocytes and upon activation triggers anti-inflammatory pathways. The aim of this research was to identify anti-inflammatory mediators that may participate in the immunomodulatory effects of melanocortins in glial cells. Since peroxisome proliferator-activated receptors (PPARs) have recently been implicated in the modulation of inflammation, we investigated the effect of an α-MSH analog, [Nle4, D-Phe7]-α-MSH (NDP-α-MSH), on PPAR-β and PPAR-γ gene and protein expression in rat primary astrocytes and microglia. We initially demonstrated that rat primary microglia express MC4R and showed that treatment with NDP-α-MSH increases PPAR-γ protein levels and strongly decreases PPAR-β levels in both astrocytes and microglia. We also showed that extracellular signal-regulated kinase 1/2 (ERK1/2)–mediated signaling is partially involved in these effects in a cell-specific fashion. Finally, we showed that NDP-α-MSH stimulates the release of the anti-inflammatory cytokines IL-10 and TGF-β from microglia and astrocytes, respectively. The presented data suggest a role for IL-10 and TGF-β in the protective action of melanocortins and a connection between MC4R pathway and that of the nuclear receptor PPAR-γ. This is the first report providing evidence that MC4R is expressed in rat primary microglia and that melanocortins modulate PPAR levels in glial cells. Our findings provide new insights into the mechanisms underlying the activation of glial MC4R and open perspectives for new therapeutic strategies for the treatment of inflammation-mediated brain diseases. PMID:23468969

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses*

PubMed Central

Huo, Yuqing; Guo, Xin; Li, Honggui; Xu, Hang; Halim, Vera; Zhang, Weiyu; Wang, Huan; Fan, Yang-Yi; Ong, Kuok Teong; Woo, Shih-Lung; Chapkin, Robert S.; Mashek, Douglas G.; Chen, Yanming; Dong, Hui; Lu, Fuer; Wei, Lai; Wu, Chaodong

2012-01-01

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues. Compared with wild-type littermates (controls) on a high fat diet (HFD), Tg mice exhibited increased adiposity, decreased adipose inflammatory response, and improved insulin sensitivity. In a parallel pattern, HFD-fed Tg mice showed increased hepatic steatosis, decreased liver inflammatory response, and improved liver insulin sensitivity compared with controls. In both adipose and liver tissues, increased fat deposition was associated with lipid profile alterations characterized by an increase in palmitoleate. Additionally, plasma lipid profiles also displayed an increase in palmitoleate in HFD-Tg mice compared with controls. In cultured 3T3-L1 adipocytes, overexpression of PFKFB3/iPFK2 recapitulated metabolic and inflammatory changes observed in adipose tissue of Tg mice. Upon treatment with conditioned medium from iPFK2-overexpressing adipocytes, mouse primary hepatocytes displayed metabolic and inflammatory responses that were similar to those observed in livers of Tg mice. Together, these data demonstrate a unique role for PFKFB3/iPFK2 in adipocytes with regard to diet-induced inflammatory responses in both adipose and liver tissues. PMID:22556414

α-Fetoprotein as a modulator of the pro-inflammatory response of human keratinocytes

PubMed Central

Potapovich, AI; Pastore, S; Kostyuk, VA; Lulli, D; Mariani, V; De Luca, C; Dudich, EI; Korkina, LG

2009-01-01

Background and purpose: The immunomodulatory effects of α-fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA- and cytokine-induced pro-inflammatory responses of human keratinocytes. Experimental approach: Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFκB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFκB DNA binding activity was measured by specific assays. Nitric oxide and H2O2 production and redox status were assessed by fluorescent probe and biochemical methods. Key results: All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose-dependently increased tumour necrosis factor alpha-stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha-induced monocyte chemotactic protein 1 and IP-10 (interferon gamma-produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H2O2 and modulated nitrite/nitrate levels in non-stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA-stimulated cells. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Akt1 but not NFκB was activated by AFP alone or by its combination with UVA. Conclusions and implications: Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro-inflammatory mediators and modulation of their pro-inflammatory response to cytokines or UVA. AFP may modulate inflammatory events in human skin. PMID:19785658

Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences.

PubMed

Donzis, Elissa J; Tronson, Natalie C

2014-11-01

This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition. Copyright © 2014 Elsevier Inc. All rights reserved.

Grape polyphenols and propolis mixture inhibits inflammatory mediator release from human leukocytes and reduces clinical scores in experimental arthritis.

PubMed

Mossalayi, M D; Rambert, J; Renouf, E; Micouleau, M; Mérillon, J M

2014-02-15

Polyphenols from red fruits and bee-derived propolis (PR) are bioactive natural products in various in vitro and in vivo models. The present study shows that hematotoxicity-free doses of grape polyphenols (GPE) and PR differentially decreased the secretion of pro-inflammatory cytokines from activated human peripheral blood leucocytes. While GPE inhibited the monocytes/macrophage response, propolis decreased both monokines and interferon γ (IFNγ) production. When used together, their distinct effects lead to the attenuation of all inflammatory mediators, as supported by a significant modulation of the transcriptomic profile of pro-inflammatory genes in human leukocytes. To enforce in vitro data, GPE+PR were tested for their ability to improve clinical scores and cachexia in chronic rat adjuvant-induced arthritis (AA). Extracts significantly reduced arthritis scores and cachexia, and this effect was more significant in animals receiving continuous low doses compared to those receiving five different high doses. Animals treated daily had significantly better clinical scores than corticoid-treated rats. Together, these findings indicate that the GPE+PR combination induces potent anti-inflammatory activity due to their complementary immune cell modulation. Copyright © 2013 Elsevier GmbH. All rights reserved.

2-Pentadecyl-2-Oxazoline, the Oxazoline of Pea, Modulates Carrageenan-Induced Acute Inflammation

PubMed Central

Petrosino, Stefania; Campolo, Michela; Impellizzeri, Daniela; Paterniti, Irene; Allarà, Marco; Gugliandolo, Enrico; D’Amico, Ramona; Siracusa, Rosalba; Cordaro, Marika; Esposito, Emanuela; Di Marzo, Vincenzo; Cuzzocrea, Salvatore

2017-01-01

N-acylethanolamines (NAEs) involve a family of lipid molecules existent in animal and plant, with N-palmitoylethanolamide (PEA) that arouses great attention owing to its anti-inflammatory, analgesic and neuroprotective activities. Because PEA is produced on demand and exerts pleiotropic effects, the modulation of specific amidases for NAEs (and in particular NAE-hydrolyzing acid amidase NAAA, which is more selective for PEA) could be a condition to preserve its levels. Here we investigate the effect of 2-Pentadecyl-2-oxazoline (PEA-OXA) the oxazoline of PEA, on human recombinant NAAA in vitro and in an established model of Carrageenan (CAR)-induced rat paw inflammation. PEA-OXA dose-dependently significantly inhibited recombinant NAAA and, orally administered to rats (10 mg/kg), limiting histological damage, thermal hyperalgesia and the increase of infiltrating inflammatory cells after CAR injection in the rat right hindpaw, compared to ultramicronized PEA given orally at the same dose (10 mg/kg). These effects were accompanied by elevation of paw PEA levels. Moreover, PEA-OXA markedly reduced neutrophil infiltration and pro-inflammatory cytokine release and prevented CAR-induced IκB-α degradation, nuclear translocation of NF-κB p65, the increase of inducible nitric oxide synthase, cyclooxygenase-2, intercellular adhesion molecule-1, and mast cell activation. Experiments in PPAR-α knockout mice showed that the anti-inflammatory effects of PEA-OXA were not dependent on the presence of PPAR-α receptors. In conclusion, NAAA modulators as PEA-OXA could help to maximize the tissue availability of PEA by increasing its levels and anti-inflammatory effects. PMID:28611664

Modulation of the cyclooxygenase pathway via inhibition of nitric oxide production contributes to the anti-inflammatory activity of kaempferol.

PubMed

Mahat, Mahamad Yunnus A; Kulkarni, Nagaraj M; Vishwakarma, Santosh L; Khan, Farhin R; Thippeswamy, B S; Hebballi, Vijay; Adhyapak, Anjana A; Benade, Vijay S; Ashfaque, Saudagar Mohammad; Tubachi, Suraj; Patil, Basangouda M

2010-09-10

Kaempferol has been reported to inhibit nitric oxide synthase and cyclooxygenase enzymes in animal models. The present study was designed to investigate whether kaempferol modulates the cyclooxygenase pathway via inhibition of nitric oxide production, which in turn contributes to its anti-inflammatory activity. Investigations were performed using carrageenan induced rat air pouch model. Inflammation was assessed by measurement of nitrites (nitrite, a breakdown product of nitric oxide), prostaglandin-E(2) levels and cellular infiltration in the pouch fluid exudates. To assess the anti-inflammatory effect of the extract, rat air pouch linings were examined histologically. The levels of nitrite and prostaglandin-E(2) in pouch fluid were measured by using Griess assay and ELISA respectively. Cell counts and differential counts were performed using a Coulter counter and Wright-Giemsa stain respectively. Kaempferol when administered orally at 50 and 100mg/kg dose showed significant inhibition of carrageenan induced production of nitrite (40.12 and 59.74%, respectively) and prostaglandin-E(2) generation (64.23 and 78.55%, respectively). Infiltration of the cells into the rat granuloma air pouch was also significantly inhibited by kaempferol. Modulation of cyclooxygenase pathway via inhibition of nitric oxide synthesis significantly contributes to kaempferol's anti-inflammatory activity. The present study characterizes the effects and mechanisms of naturally occurring phenolic flavonoid kaempferol, on inducible nitric oxide synthase expression and nitric oxide production. These results partially explain the pharmacological efficacy of flavonoids in general and kaempferol in particular as anti-inflammatory compounds. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Modulation of Invading and Resident Inflammatory Cell Activation as a Novel Way to Mitigate Spinal Cord Injury-Associated Neuropathic Pain

DTIC Science & Technology

2017-09-01

alcohol consumption alone and in combination with SCI on the same inflammatory and neuropathic endpoints, as well as the ameliorative effects of CBD...inflammatory outcomes: 100% complete CY16 Goals Quantify markers following alcohol consumption : 100% complete Investigate combined alcohol/SCI...events such as generation of reactive oxygen and nitrogen species, chemokine and cytokine release, microglial and astrocytic activation, and T cell

Gut Microbiota: A Key Modulator of Intestinal Healing in Inflammatory Bowel Disease.

PubMed

Lopetuso, L R; Petito, V; Zambrano, D; Orlando, D; Dal Lago, A; Serrichhio, L; Papa, A; Gasbarrini, A; Scaldaferri, F

2016-01-01

Mucosal healing (MH) represents a crucial factor for maintaining gut homeostasis. Indeed, in inflammatory bowel disease, MH has become the standard therapeutical target, because it is associated with more effective disease control, more frequent steroid-free remission, lower rates of hospitalization and surgery, and improved quality of life. In this scenario, gut microbiota is a crucial player in modulating intestinal repair and regeneration process. It can act on the tumor necrosis factor-α production, modulation of reactive oxygen and nitrogen species, activity of matrix metalloproteinases and on many other mechanisms strictly involved in restoring gut health. In this review, we analyze and review the literature on the role of gut microbiota in sustaining mucosal injury and achieving MH. © 2016 S. Karger AG, Basel.

Topical Modulation of the Burn Wound Inflammatory Response to Improve Short and Long Term Outcomes

DTIC Science & Technology

2016-10-01

Duroc pig. We hypothesize that topical p38MAPK inhibition will attenuate the depth of the burn by preventing hair -follicle cell apoptosis, attenuate...Intracellular MAPK Hair -Follicle Apoptosis Local/Dermal Inflammatory Cell Activation SIRS End-Organ Failure Topical MAPK Inhibitors Production of

Modulation of inflammation in transgenic models of Alzheimer’s disease

PubMed Central

2014-01-01

Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer’s disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Aβ) generation, Aβ aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Aβ levels by these inflammatory mediators. PMID:24490742

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

VIP impairs acquisition of the macrophage proinflammatory polarization profile.

PubMed

Carrión, Mar; Pérez-García, Selene; Martínez, Carmen; Juarranz, Yasmina; Estrada-Capetillo, Lizbeth; Puig-Kröger, Amaya; Gomariz, Rosa P; Gutiérrez-Cañas, Irene

2016-12-01

This study tested the hypothesis that vasoactive intestinal peptide (VIP) is able to modify the macrophage inflammatory profile, thus supporting its therapeutic role in autoimmune diseases. Macrophages are innate immune cells that display a variety of functions and inflammatory profiles in response to the environment that critically controls their polarization. Deregulation between the pro- and anti-inflammatory phenotypes has been involved in different pathologies. Rheumatoid arthritis (RA) is an autoimmune disease, in which macrophages are considered central effectors of synovial inflammation, displaying a proinflammatory profile. VIP is a pleiotropic neuropeptide with proven anti-inflammatory actions. As modulation of the macrophage phenotype has been implicated in the resolution of inflammatory diseases, we evaluated whether VIP is able to modulate human macrophage polarization. In vitro-polarized macrophages by GM-CSF (GM-MØ), with a proinflammatory profile, expressed higher levels of VIP receptors, vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2, respectively), than macrophages polarized by M-CSF (M-MØ) with anti-inflammatory activities. RA synovial macrophages, according to their GM-CSF-like polarization state, expressed both VPAC1 and VPAC2. In vitro-generated GM-MØ exposed to VIP exhibited an up-regulation of M-MØ gene marker expression, whereas their proinflammatory cytokine profile was reduced in favor of an anti-inflammatory function. Likewise, in GM-MØ, generated in the presence of VIP, VIP somehow changes the macrophages physiology profile to a less-damaging phenotype. Therefore, these results add new value to VIP as an immunomodulatory agent on inflammatory diseases. © Society for Leukocyte Biology.

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

Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining anti-inflammatory, immunomodulatory and antioxidant activities.

PubMed

Bansal, Yogita; Silakari, Om

2014-11-01

Polyfunctional compounds comprise a novel class of therapeutic agents for treatment of multifactorial diseases. The present study reports a series of benzimidazole-non-steroidal anti-inflammatory drugs (NSAIDs) conjugates (1-10) as novel polyfunctional compounds synthesized in the presence of orthophosphoric acid. The compounds were evaluated for anti-inflammatory (carageenan-induced paw edema model), immunomodulatory (direct haemagglutination test and carbon clearance index models), antioxidant (in vitro and in vivo) and for ulcerogenic effects. Each of the compound has retained the anti-inflammatory activity of the corresponding parent NSAID while exhibiting significantly reduced gastric ulcers. Additionally, the compounds are found to possess potent immunostimulatory and antioxidant activities. The compound 8 was maximally potent (antibody titre value 358.4 ± 140.21, carbon clearance index 0.053 ± 0.002 and antioxidant EC50 value 0.03 ± 0.006). These compounds, exhibiting such multiple pharmacological activities, can be taken as lead for the development of potent drugs for the treatment of chronic multifactorial diseases involving inflammation, immune system modulation and oxidative stress such as cancers. The Lipinski's parameters suggested the compounds to be bear drug like properties.

Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients.

PubMed

Conroy, Melissa J; Galvin, Karen C; Doyle, Suzanne L; Kavanagh, Maria E; Mongan, Ann-Marie; Cannon, Aoife; Moore, Gillian Y; Reynolds, John V; Lysaght, Joanne

2016-10-01

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69(+) and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.

Acupuncture to Reduce HIV-Associated Inflammation

PubMed Central

Swanson, Barbara; Keithley, Joyce K.; Johnson, Angela; Fogg, Louis; Adeyemi, Oluwatoyin; Sha, Beverly E.; Snell, Kimberly A.

2015-01-01

Background. HIV infection is associated with systemic inflammation that can increase risk for cardiovascular events. Acupuncture has been shown to have immunomodulatory effects and to improve symptoms in persons with inflammatory conditions. Objective. To test the anti-inflammatory effects of an acupuncture protocol that targets the cholinergic anti-inflammatory pathway (CAIP), a neural mechanism whose activation has been shown to reduce the release of proinflammatory cytokines, in persons with HIV-associated inflammation. Design, Setting, Participants, and Interventions. Double-blind, placebo-controlled clinical trial conducted in an outpatient clinic located in a medically underserved urban neighborhood. Twenty-five clinically-stable HIV-infected persons on antiretroviral therapy were randomized to receive once weekly CAIP-based acupuncture or sham acupuncture. Main Outcome Measures. Outcomes included plasma concentrations of high sensitivity C-reactive protein and D-dimer and fasting lipids. Results. Twenty-five participants completed the protocol (treatment group n = 12, control group n = 13). No adverse events related to the acupuncture protocol were observed. Compared to baseline values, the two groups did not significantly differ in any outcome measures at the end of the acupuncture protocol. Conclusions. CAIP-based acupuncture did not favorably modulate inflammatory or lipid parameters. Additional studies are warranted of CAIP-based protocols of different frequencies/durations. PMID:25922615

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.

Therapeutic Use of Cannabis in Inflammatory Bowel Disease

PubMed Central

Katz, Seymour

2016-01-01

The marijuana plant Cannabis sativa and its derivatives, cannabinoids, have grown increasingly popular as a potential therapy for inflammatory bowel disease (IBD). Studies have shown that modulation of the endocannabinoid system, which regulates various functions in the body and has been shown to play a key role in the pathogenesis of IBD, has a therapeutic effect in mouse colitis. Epidemiologic data and human therapy studies reveal a possible role for cannabinoids in the symptomatic treatment of IBD, although it has yet to be determined in human populations whether cannabinoids have therapeutic anti-inflammatory effects in IBD or are simply masking its many debilitating symptoms. Large, double-blind, randomized, placebo-controlled trials using serial inflammatory markers, biopsy findings, and endoscopic disease severity to demonstrate objective improvement in IBD are necessary before cannabis can be empirically accepted and recommended as an IBD treatment option. Questions concerning its safety profile and adverse effects prompt the need for further research, particularly in regard to dosing and route of administration to maximize benefits and limit potential harms. Cannabis use should be reserved for symptomatic control in patients with severe IBD refractory to the currently available standard-of-care and complementary and alternative medicines. PMID:28035196

Effects of permafrost microorganisms on skin wound reparation.

PubMed

Kalenova, L F; Novikova, M A; Subbotin, A M

2015-02-01

Local application of ointment with Bacillus spp. strain MG8 (15,000-20,000 living bacterial cells), isolated from permafrost specimens, on the skin wound of about 60 mm(2) stimulated the reparation processes in experimental mice. A possible mechanism stimulating the regeneration of the damaged tissues under the effect of MG8 could be modulation of the immune system reactivity with more rapid switchover to humoral immunity anti-inflammatory mechanisms aimed at de novo synthesis of protein.

Abdominal adiposity is the main determinant of the C-reactive response to injury in subjects undergoing inguinal hernia repair

PubMed Central

2013-01-01

Background Obesity and serum C-reactive protein (CRP) (a sensitive marker of inflammatory activity) are associated with most chronic diseases. Abdominal adiposity along with age is the strongest determinant of baseline CRP levels in healthy subjects. The mechanism of the association of serum CRP with disease is uncertain. We hypothesized that baseline serum CRP is a marker of inflammatory responsiveness to injury and that abdominal adiposity is the main determinant of this responsiveness. We studied the effect of abdominal adiposity, age and other environmental risk factors for chronic disease on the CRP response to a standardised surgical insult, unilateral hernia repair to not only test this hypothesis but to inform the factors which must be taken into account when assessing systemic inflammatory responses to surgery. Methods 102 male subjects aged 24-94 underwent unilateral hernia repair by a single operator. CRP was measured at 0, 6, 24 and 48 hrs. Response was defined as the peak CRP adjusted for baseline CRP. Results Age and waist:hip ratio (WHR) were associated both with basal CRP and CRP response with similar effect sizes after adjustment for a wide-range of covariates. The adjusted proportional difference in CRP response per 10% increase in WHR was 1.50 (1.17-1.91) p = 0.0014 and 1.15(1.00-1.31) p = 0.05 per decade increase in age. There was no evidence of important effects of other environmental cardiovascular risk factors on CRP response. Conclusion Waist:hip ratio and age need to be considered when studying the inflammatory response to surgery. The finding that age and waist:hip ratio influence baseline and post-operative CRP levels to a similar extent suggests that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that higher age and obesity modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery. The mechanism for the association of baseline CRP and waist:hip ratio to chronic disease outcomes could be through this increase in inflammatory system excitability. PMID:23391158

Modulation of experimental arthritis by vagal sensory and central brain stimulation.

PubMed

Bassi, Gabriel Shimizu; Dias, Daniel Penteado Martins; Franchin, Marcelo; Talbot, Jhimmy; Reis, Daniel Gustavo; Menezes, Gustavo Batista; Castania, Jaci Airton; Garcia-Cairasco, Norberto; Resstel, Leonardo Barbosa Moraes; Salgado, Helio Cesar; Cunha, Fernando Queiróz; Cunha, Thiago Mattar; Ulloa, Luis; Kanashiro, Alexandre

2017-08-01

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations. Copyright © 2017 Elsevier Inc. All rights reserved.

Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels

PubMed Central

Xu, Jian Hui; Liu, Xing Zhen; Pan, Wei; Zou, Da Jin

2017-01-01

Systemic inflammation, which can be induced by metabolic endotoxemia, and corresponding high-fat diet-mediated metabolic disorders are associated with gut microbiota. In the present study reverse transcription-polymerase chain reaction, immunofluorescence, pyrosequencing, ELISA and Oil Red O staining were performed to assess whether berberine can protect against diet-induced obesity, through modulating the gut microbiota and consequently improving metabolic endotoxemia and gastrointestinal hormone levels. Alterations in the gut microbiota induced by berberine resulted in a significant reduction in bacterial lipopolysaccharide levels in portal plasma. Levels of inflammatory and oxidative stress markers, as well as the mRNA expression levels of macrophage infiltration markers in visceral adipose tissue, were also reduced by berberine. Inhibition of the inflammatory response was associated with a reduction in intestinal permeability and an increase in the expression of tight junction proteins. In addition, berberine was reported to restore aberrant levels of gut hormones in the portal plasma, such as glucagon-like peptide-1 and −2, peptide YY, glucose-dependent insulinotropic polypeptide and pancreatic polypeptide. The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia and systemic inflammation, and improved gut peptide levels in high-fat diet-fed rats. The present study suggests that berberine may be an effective therapeutic strategy for the treatment of obesity and insulin resistance. PMID:28447763

Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels.

PubMed

Xu, Jian Hui; Liu, Xing Zhen; Pan, Wei; Zou, Da Jin

2017-05-01

Systemic inflammation, which can be induced by metabolic endotoxemia, and corresponding high‑fat diet‑mediated metabolic disorders are associated with gut microbiota. In the present study reverse transcription-polymerase chain reaction, immunofluorescence, pyrosequencing, ELISA and Oil Red O staining were performed to assess whether berberine can protect against diet-induced obesity, through modulating the gut microbiota and consequently improving metabolic endotoxemia and gastrointestinal hormone levels. Alterations in the gut microbiota induced by berberine resulted in a significant reduction in bacterial lipopolysaccharide levels in portal plasma. Levels of inflammatory and oxidative stress markers, as well as the mRNA expression levels of macrophage infiltration markers in visceral adipose tissue, were also reduced by berberine. Inhibition of the inflammatory response was associated with a reduction in intestinal permeability and an increase in the expression of tight junction proteins. In addition, berberine was reported to restore aberrant levels of gut hormones in the portal plasma, such as glucagon‑like peptide‑1 and ‑2, peptide YY, glucose‑dependent insulinotropic polypeptide and pancreatic polypeptide. The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia and systemic inflammation, and improved gut peptide levels in high‑fat diet‑fed rats. The present study suggests that berberine may be an effective therapeutic strategy for the treatment of obesity and insulin resistance.

Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury.

PubMed

Langness, Simone; Costantini, Todd W; Morishita, Koji; Eliceiri, Brian P; Coimbra, Raul

2016-01-01

Trauma/hemorrhagic shock (T/HS) causes the release of pro-inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI. ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI-121. ML samples from each experimental group were injected into naïve mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment. T/HS lymph injected in naïve mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS. Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury.

Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context.

PubMed

Ruiz-Núñez, Begoña; Pruimboom, Leo; Dijck-Brouwer, D A Janneke; Muskiet, Frits A J

2013-07-01

In this review, we focus on lifestyle changes, especially dietary habits, that are at the basis of chronic systemic low grade inflammation, insulin resistance and Western diseases. Our sensitivity to develop insulin resistance traces back to our rapid brain growth in the past 2.5 million years. An inflammatory reaction jeopardizes the high glucose needs of our brain, causing various adaptations, including insulin resistance, functional reallocation of energy-rich nutrients and changing serum lipoprotein composition. The latter aims at redistribution of lipids, modulation of the immune reaction, and active inhibition of reverse cholesterol transport for damage repair. With the advent of the agricultural and industrial revolutions, we have introduced numerous false inflammatory triggers in our lifestyle, driving us to a state of chronic systemic low grade inflammation that eventually leads to typically Western diseases via an evolutionary conserved interaction between our immune system and metabolism. The underlying triggers are an abnormal dietary composition and microbial flora, insufficient physical activity and sleep, chronic stress and environmental pollution. The disturbance of our inflammatory/anti-inflammatory balance is illustrated by dietary fatty acids and antioxidants. The current decrease in years without chronic disease is rather due to "nurture" than "nature," since less than 5% of the typically Western diseases are primary attributable to genetic factors. Resolution of the conflict between environment and our ancient genome might be the only effective manner for "healthy aging," and to achieve this we might have to return to the lifestyle of the Paleolithic era as translated to the 21st century culture. Copyright © 2013 Elsevier Inc. All rights reserved.

Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

PubMed Central

Szabo, Attila; Kovacs, Attila

2014-01-01

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor. PMID:25171370

Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.

PubMed

Szabo, Attila; Kovacs, Attila; Frecska, Ede; Rajnavolgyi, Eva

2014-01-01

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

The inflammatory protein Pentraxin 3 in cardiovascular disease.

PubMed

Fornai, Francesco; Carrizzo, Albino; Forte, Maurizio; Ambrosio, Mariateresa; Damato, Antonio; Ferrucci, Michela; Biagioni, Francesca; Busceti, Carla; Puca, Annibale A; Vecchione, Carmine

2016-01-01

The acute phase protein Pentraxin 3 (PTX3) plays a non-redundant role as a soluble pattern recognition receptor for selected pathogens and it represents a rapid biomarker for primary local activation of innate immunity and inflammation. Recent evidence indicates that PTX3 exerts an important role in modulating the cardiovascular system in humans and experimental models. In particular, there are conflicting points concerning the effects of PTX3 in cardiovascular diseases (CVD) since several observations indicate a cardiovascular protective effect of PTX3 while others speculate that the increased plasma levels of PTX3 in subjects with CVD correlate with disease severity and with poor prognosis in elderly patients. In the present review, we discuss the multifaceted effects of PTX3 on the cardiovascular system focusing on its involvement in atherosclerosis, endothelial function, hypertension, myocardial infarction and angiogenesis. This may help to explain how the specific modulation of PTX3 such as the use of different dosing, time, and target organs could help to contain different vascular diseases. These opposite actions of PTX3 will be emphasized concerning the modulation of cardiovascular system where potential therapeutic implications of PTX3 in humans are discussed.

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

PubMed Central

Mahapatra, Saugata; Gallaher, Brandi; Smith, Sydni Caet; Graham, Joseph G.; Voth, Daniel E.; Shaw, Edward I.

2016-01-01

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth. PMID:28066723

Effects of short-term dietary restriction and glutamine supplementation in vitro on the modulation of inflammatory properties.

PubMed

C de Oliveira, Dalila; Santos, Ed Wilson; Nogueira-Pedro, Amanda; Xavier, José Guilherme; Borelli, Primavera; Fock, Ricardo Ambrósio

2018-04-01

Dietary restriction (DR) is a nutritional intervention that exerts profound effects on biochemical and immunologic parameters, modulating some inflammatory properties. Glutamine (GLN) is a conditionally essential amino acid that can modulate inflammatory properties. However, there is a lack of data evaluating the effects of DR and GLN supplementation, especially in relation to inflammatory cytokine production and the expression of transcription factors such as nuclear factor (NF)-κB. We subjected 3-mo-old male Balb/c mice to DR by reducing their food intake by 30%. DR animals lost weight and showed reduced levels of serum triacylglycerols, glucose, cholesterol, and calcium as well as a reduction in bone density. Additionally, blood, peritoneal, and spleen cellularity were reduced, lowering the number of peritoneal F4/80- and CD86-positive cells and the total number of splenic CD4- and CD8-positive cells. The production of interleukin (IL)-10 and the expression of NF-κB in splenic cells were not affected by DR or by GLN supplementation. However, peritoneal macrophages from DR animals showed reduced IL-12 and tumor necrosis factor-α production and increased IL-10 production with reduced phosphorylation of NF-κB expression. Additionally, GLN was able to modulate cytokine production by peritoneal cells from the control group, although no effects were observed in cells from the DR group. DR induces biochemical and immunologic changes, in particular by reducing IL-12 and tumor necrosis factor-α production by macrophages and clearly upregulating IL-10 production, whereas GLN supplementation did not modify these parameters in cells from DR animals. Copyright © 2017 Elsevier Inc. All rights reserved.

Immunomodulation and Anti-Inflammatory Effects of Garlic Compounds

PubMed Central

Arreola, Rodrigo; Quintero-Fabián, Saray; López-Roa, Rocío Ivette; Flores-Gutiérrez, Enrique Octavio; Reyes-Grajeda, Juan Pablo; Carrera-Quintanar, Lucrecia; Ortuño-Sahagún, Daniel

2015-01-01

The benefits of garlic to health have been proclaimed for centuries; however, only recently have Allium sativum and its derivatives been proposed as promising candidates for maintaining the homeostasis of the immune system. The complex biochemistry of garlic makes it possible for variations in processing to yield different preparations with differences in final composition and compound proportion. In this review, we assess the most recent experimental results, which indicate that garlic appears to enhance the functioning of the immune system by stimulating certain cell types, such as macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils, by mechanisms including modulation of cytokine secretion, immunoglobulin production, phagocytosis, and macrophage activation. Finally, because immune dysfunction plays an important role in the development and progress of several diseases, we critically examined immunoregulation by garlic extracts and compounds isolated, which can contribute to the treatment and prevention of pathologies such as obesity, metabolic syndrome, cardiovascular disorders, gastric ulcer, and even cancer. We concluded that A. sativum modulates cytokine secretion and that such modulation may provide a mechanism of action for many of their therapeutic effects. PMID:25961060

Immunomodulation and anti-inflammatory effects of garlic compounds.

PubMed

Arreola, Rodrigo; Quintero-Fabián, Saray; López-Roa, Rocío Ivette; Flores-Gutiérrez, Enrique Octavio; Reyes-Grajeda, Juan Pablo; Carrera-Quintanar, Lucrecia; Ortuño-Sahagún, Daniel

2015-01-01

The benefits of garlic to health have been proclaimed for centuries; however, only recently have Allium sativum and its derivatives been proposed as promising candidates for maintaining the homeostasis of the immune system. The complex biochemistry of garlic makes it possible for variations in processing to yield different preparations with differences in final composition and compound proportion. In this review, we assess the most recent experimental results, which indicate that garlic appears to enhance the functioning of the immune system by stimulating certain cell types, such as macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils, by mechanisms including modulation of cytokine secretion, immunoglobulin production, phagocytosis, and macrophage activation. Finally, because immune dysfunction plays an important role in the development and progress of several diseases, we critically examined immunoregulation by garlic extracts and compounds isolated, which can contribute to the treatment and prevention of pathologies such as obesity, metabolic syndrome, cardiovascular disorders, gastric ulcer, and even cancer. We concluded that A. sativum modulates cytokine secretion and that such modulation may provide a mechanism of action for many of their therapeutic effects.

Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders.

PubMed

Ghasemi, Mehdi; Phillips, Cristy; Fahimi, Atoossa; McNerney, Margaret Windy; Salehi, Ahmad

2017-09-01

Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-d-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials. Altogether, these studies establish a warrant for the refinement of novel compounds that target glutamatergic mechanisms for the treatment of MDs. Published by Elsevier Ltd.

Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator.

PubMed

Font, Joan; López-Cano, Marc; Notartomaso, Serena; Scarselli, Pamela; Di Pietro, Paola; Bresolí-Obach, Roger; Battaglia, Giuseppe; Malhaire, Fanny; Rovira, Xavier; Catena, Juanlo; Giraldo, Jesús; Pin, Jean-Philippe; Fernández-Dueñas, Víctor; Goudet, Cyril; Nonell, Santi; Nicoletti, Ferdinando; Llebaria, Amadeu; Ciruela, Francisco

2017-04-11

Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu 5 ) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug's release, which effectively controls mGlu 5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu 5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders.

Therapeutic Potential of Targeting the Ghrelin Pathway.

PubMed

Colldén, Gustav; Tschöp, Matthias H; Müller, Timo D

2017-04-11

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems' metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.

Signed, Sealed, Delivered: Microenvironmental Modulation of Extracellular Vesicle-Dependent Immunoregulation in the Lung.

PubMed

Schneider, Daniel J; Speth, Jennifer M; Peters-Golden, Marc

2016-01-01

Unconventional secretion and subsequent uptake of molecular cargo via extracellular vesicles (EVs) is an important mechanism by which cells can exert paracrine effects. While this phenomenon has been widely characterized in the context of their ability to promote inflammation, less is known about the ability of EVs to transfer immunosuppressive cargo. Maintenance of normal physiology in the lung requires suppression of potentially damaging inflammatory responses to the myriad of insults to which it is continually exposed. Recently, our laboratory has reported the ability of alveolar macrophages (AMs) to secrete suppressors of cytokine signaling (SOCS) proteins within microvesicles (MVs) and exosomes (Exos). Uptake of these EVs by alveolar epithelial cells (AECs) resulted in inhibition of pro-inflammatory STAT activation in response to cytokines. Moreover, AM packaging of SOCS within EVs could be rapidly tuned in response to exogenous or AEC-derived substances. In this article we will highlight gaps in knowledge regarding microenvironmental modulation of cargo packaging and utilization as well as EV secretion and uptake. Advances in these areas are critical for improving understanding of intercellular communication in the immune system and for therapeutic application of artificial vesicles aimed at treatment of diseases characterized by dysregulated inflammation.

Signed, Sealed, Delivered: Microenvironmental Modulation of Extracellular Vesicle-Dependent Immunoregulation in the Lung

PubMed Central

Schneider, Daniel J.; Speth, Jennifer M.; Peters-Golden, Marc

2016-01-01

Unconventional secretion and subsequent uptake of molecular cargo via extracellular vesicles (EVs) is an important mechanism by which cells can exert paracrine effects. While this phenomenon has been widely characterized in the context of their ability to promote inflammation, less is known about the ability of EVs to transfer immunosuppressive cargo. Maintenance of normal physiology in the lung requires suppression of potentially damaging inflammatory responses to the myriad of insults to which it is continually exposed. Recently, our laboratory has reported the ability of alveolar macrophages (AMs) to secrete suppressors of cytokine signaling (SOCS) proteins within microvesicles (MVs) and exosomes (Exos). Uptake of these EVs by alveolar epithelial cells (AECs) resulted in inhibition of pro-inflammatory STAT activation in response to cytokines. Moreover, AM packaging of SOCS within EVs could be rapidly tuned in response to exogenous or AEC-derived substances. In this article we will highlight gaps in knowledge regarding microenvironmental modulation of cargo packaging and utilization as well as EV secretion and uptake. Advances in these areas are critical for improving understanding of intercellular communication in the immune system and for therapeutic application of artificial vesicles aimed at treatment of diseases characterized by dysregulated inflammation. PMID:27626032

Endophenotype Network Models: Common Core of Complex Diseases

PubMed Central

Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I.; Giulianini, Franco; Wang, Ruisheng; Ricchiuto, Piero; Aikawa, Masanori; Iwata, Hiroshi; Müller, Christian; Zeller, Tania; Sharma, Amitabh; Wild, Philipp; Lackner, Karl; Singh, Sasha; Ridker, Paul M.; Blankenberg, Stefan; Barabási, Albert-László; Loscalzo, Joseph

2016-01-01

Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules. PMID:27278246

Endophenotype Network Models: Common Core of Complex Diseases

NASA Astrophysics Data System (ADS)

Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I.; Giulianini, Franco; Wang, Ruisheng; Ricchiuto, Piero; Aikawa, Masanori; Iwata, Hiroshi; Müller, Christian; Zeller, Tania; Sharma, Amitabh; Wild, Philipp; Lackner, Karl; Singh, Sasha; Ridker, Paul M.; Blankenberg, Stefan; Barabási, Albert-László; Loscalzo, Joseph

2016-06-01

Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

Modulation of neuroinflammation: Role and therapeutic potential of TRPV1 in the neuro-immune axis.

PubMed

Kong, Wei-Lin; Peng, Yuan-Yuan; Peng, Bi-Wen

2017-08-01

Transient receptor potential vanilloid type 1 channel (TRPV1), as a ligand-gated non-selective cation channel, has recently been demonstrated to have wide expression in the neuro-immune axis, where its multiple functions occur through regulation of both neuronal and non-neuronal activities. Growing evidence has suggested that TRPV1 is functionally expressed in glial cells, especially in the microglia and astrocytes. Glial cells perform immunological functions in response to pathophysiological challenges through pro-inflammatory or anti-inflammatory cytokines and chemokines in which TRPV1 is involved. Sustaining inflammation might mediate a positive feedback loop of neuroinflammation and exacerbate neurological disorders. Accumulating evidence has suggested that TRPV1 is closely related to immune responses and might be recognized as a molecular switch in the neuroinflammation of a majority of seizures and neurodegenerative diseases. In this review, we evidenced that inflammation modulates the expression and activity of TRPV1 in the central nervous system (CNS) and TRPV1 exerts reciprocal actions over neuroinflammatory processes. Together, the literature supports the hypothesis that TRPV1 may represent potential therapeutic targets in the neuro-immune axis. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigating the role of charge on cotton materials designed to intervene in the hemostatic and inflammatory stages of wound healing

USDA-ARS?s Scientific Manuscript database

Recent developments in cellulose wound dressings targeted to different stages of wound healing have been based on structural and charge modifications that function to modulate events in the complex inflammatory and haemostatic phases of wound healing. Hemostasis and inflammation comprise two overlap...

Tilmicosin and tylosin have anti-inflammatory properties via modulation of COX-2 and iNOS gene expression and production of cytokines in LPS-induced macrophages and monocytes.

PubMed

Cao, Xing-Yuan; Dong, Mei; Shen, Jian-Zhong; Wu, Bei-Bei; Wu, Cong-Ming; Du, Xiang-Dang; Wang, Zhuo; Qi, Yi-Tao; Li, Bing-Yu

2006-05-01

Macrolides have been reported to modify the host immune and inflammatory responses both in vivo and in vitro. We examined the in vitro effect of the macrolides tilmicosin and tylosin, which are only used in the veterinary clinic, on the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)) and cytokines by lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse peripheral blood mononuclear cells (PBMCs). Compared with 5 microg/mL, tilmicosin and tylosin concentrations of 10 microg/mL and 20 microg/mL significantly decreased the production of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), PGE(2), NO, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, and increased IL-10 production. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression were also significantly reduced. These results support the opinion that macrolides may exert an anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process.

β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli.

PubMed

Bramwell, Kenneth K C; Mock, Kelton; Ma, Ying; Weis, John H; Teuscher, Cory; Weis, Janis J

2015-08-15

The lysosomal enzyme β-glucuronidase (Gusb) is a key regulator of Lyme-associated and K/B×N-induced arthritis severity. The luminal enzymes present in lysosomes provide essential catabolic functions for the homeostatic degradation of a variety of macromolecules. In addition to this essential catabolic function, lysosomes play important roles in the inflammatory response following infection. Secretory lysosomes and related vesicles can participate in the inflammatory response through fusion with the plasma membrane and release of bioactive contents into the extracellular milieu. In this study, we show that GUSB hypomorphism potentiates lysosomal exocytosis following inflammatory stimulation. This leads to elevated secretion of lysosomal contents, including glycosaminoglycans, lysosomal hydrolases, and matrix metalloproteinase 9, a known modulator of Lyme arthritis severity. This mechanistic insight led us to test the efficacy of rapamycin, a drug known to suppress lysosomal exocytosis. Both Lyme and K/B×N-associated arthritis were suppressed by this treatment concurrent with reduced lysosomal release. Copyright © 2015 by The American Association of Immunologists, Inc.

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

PubMed

Moghadasian, Mohammed H; Zhao, Ruozhi; Ghazawwi, Nora; Le, Khuong; Apea-Bah, Franklin B; Beta, Trust; Shen, Garry X

2017-10-18

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension.

PubMed

Harbaum, Lars; Renk, Emilia; Yousef, Sara; Glatzel, Antonia; Lüneburg, Nicole; Hennigs, Jan K; Oqueka, Tim; Baumann, Hans J; Atanackovic, Djordje; Grünig, Ekkehard; Böger, Rainer H; Bokemeyer, Carsten; Klose, Hans

2016-11-11

Exercise training positively influences exercise tolerance and functional capacity of patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanisms are unclear. We hypothesized that exercise modulates the activated inflammatory state found in IPAH patients. Single cardiopulmonary exercise testing was performed in 16 IPAH patients and 10 healthy subjects. Phenotypic characterization of peripheral blood mononuclear cells and circulating cytokines were assessed before, directly after and 1 h after exercise. Before exercise testing, IPAH patients showed elevated Th2 lymphocytes, regulatory T lymphocytes, IL-6, and TNF-alpha, whilst Th1/Th17 lymphocytes and IL-4 were reduced. In IPAH patients but not in healthy subject, exercise caused an immediate relative decrease of Th17 lymphocytes and a sustained reduction of IL-1-beta and IL-6. The higher the decrease of IL-6 the higher was the peak oxygen consumption of IPAH patients. Exercise seems to be safe from an immune and inflammatory point of view in IPAH patients. Our results demonstrate that exercise does not aggravate the inflammatory state and seems to elicit an immune-modulating effect in IPAH patients.

Translation repression via modulation of the cytoplasmic poly(A)-binding protein in the inflammatory response

PubMed Central

Zhang, Xu; Chen, Xiaoli; Liu, Qiuying; Zhang, Shaojie; Hu, Wenqian

2017-01-01

Gene expression is precisely regulated during the inflammatory response to control infection and limit the detrimental effects of inflammation. Here, we profiled global mRNA translation dynamics in the mouse primary macrophage-mediated inflammatory response and identified hundreds of differentially translated mRNAs. These mRNAs’ 3’UTRs have enriched binding motifs for several RNA-binding proteins, which implies extensive translational regulatory networks. We characterized one such protein, Zfp36, as a translation repressor. Using primary macrophages from a Zfp36-V5 epitope tagged knock-in mouse generated by CRISPR/Cas9-mediated genome editing, we found that the endogenous Zfp36 directly interacts with the cytoplasmic poly(A)-binding protein. Importantly, this interaction is required for the translational repression of Zfp36’s target mRNAs in resolving inflammation. Altogether, these results uncovered critical roles of translational regulations in controlling appropriate gene expression during the inflammatory response and revealed a new biologically relevant molecular mechanism of translational repression via modulating the cytoplasmic poly(A)-binding protein. DOI: http://dx.doi.org/10.7554/eLife.27786.001 PMID:28635594

Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform

PubMed Central

Nguyen, Nhung T.H.; Now, Hesung; Kim, Woo-Jong; Kim, Nari; Yoo, Joo-Yeon

2016-01-01

RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation. PMID:26996158

Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform.

PubMed

Nguyen, Nhung T H; Now, Hesung; Kim, Woo-Jong; Kim, Nari; Yoo, Joo-Yeon

2016-03-21

RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation.

Combining selected immunomodulatory Propionibacterium freudenreichii and Lactobacillus delbrueckii strains: Reverse engineering development of an anti-inflammatory cheese.

PubMed

Plé, Coline; Breton, Jérôme; Richoux, Romain; Nurdin, Marine; Deutsch, Stéphanie-Marie; Falentin, Hélène; Hervé, Christophe; Chuat, Victoria; Lemée, Riwanon; Maguin, Emmanuelle; Jan, Gwénaël; Van de Guchte, Maarten; Foligné, Benoit

2016-04-01

Inflammatory bowel disease (IBD) constitutes a growing public health concern in western countries. Bacteria with anti-inflammatory properties are lacking in the dysbiosis accompanying IBD. Selected strains of probiotic bacteria with anti-inflammatory properties accordingly alleviate symptoms and enhance treatment of ulcerative colitis in clinical trials. Such properties are also found in selected strains of dairy starters such as Propionibacterium freudenreichii and Lactobacillus delbrueckii (Ld). We thus investigated the possibility to develop a fermented dairy product, combining both starter and probiotic abilities of both lactic acid and propionic acid bacteria, designed to extend remissions in IBD patients. We developed a single-strain Ld-fermented milk and a two-strain P. freudenreichii and Ld-fermented experimental pressed cheese using strains previously selected for their anti-inflammatory properties. Consumption of these experimental fermented dairy products protected mice against trinitrobenzenesulfonic acid induced colitis, alleviating severity of symptoms, modulating local and systemic inflammation, as well as colonic oxidative stress and epithelial cell damages. As a control, the corresponding sterile dairy matrix failed to afford such protection. This work reveals the probiotic potential of this bacterial mixture, in the context of fermented dairy products. It opens new perspectives for the reverse engineering development of anti-inflammatory fermented foods designed for target populations with IBD, and has provided evidences leading to an ongoing pilot clinical study in ulcerative colitis patients. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): A prospective, randomized, double-blind study.

PubMed

Ma, C; Tsai, H; Su, W; Sun, L; Shih, Y; Wang, J

2018-05-31

Perioperative enteral nutrition (EN) enriched with immune-modulating substrates is preferable for patients undergoing major abdominal cancer surgery. In this study, perioperative EN enriched with immune-modulating nutrients such as arginine, glutamine, and omega-3 fatty acids was evaluated for its anti-inflammatory efficacy in patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST) receiving curative surgery. This prospective, randomized, double-blind study recruited 34 patients with gastric adenocarcinoma or gastric GIST undergoing elective curative surgery. These patients were randomly assigned to the study group, receiving immune-modulating nutrient-enriched EN, or the control group, receiving standard EN from 3 days before surgery (preoperative day 3) to up to postoperative day 14 or discharge. Laboratory and inflammatory parameters were assessed on preoperative day 3 and postoperative day 14 or at discharge. Adverse events (AEs) and clinical outcomes were documented daily and compared between groups. No significant differences were observed between the two groups in selected laboratory and inflammatory parameters, or in their net change, before and after treatment. AEs and clinical outcomes, including infectious complications, overall complications, time to first bowel action, and length of hospital stay after surgery, were comparable between treatment groups (all P > 0.05). Immune-modulating nutrient-enriched EN had no prominent immunomodulation effect compared with that of standard EN.

Apigenin Alleviates Endotoxin-Induced Myocardial Toxicity by Modulating Inflammation, Oxidative Stress, and Autophagy

PubMed Central

Li, Fang; Lang, Fangfang; Zhang, Huilin; Xu, Liangdong; Wang, Yidan; Zhai, Chunxiao

2017-01-01

Apigenin, a component in daily diets, demonstrates antioxidant and anti-inflammatory properties. Here, we intended to explore the mechanism of apigenin-mediated endotoxin-induced myocardial injury and its role in the interplay among inflammation, oxidative stress, and autophagy. In our lipopolysaccharide- (LPS-) induced myocardial injury model, apigenin ameliorated cardiac injury (lactate dehydrogenase (LDH) and creatine kinase (CK)), cell death (TUNEL staining, DNA fragmentation, and PARP activity), and tissue damage (cardiac troponin I (cTnI) and cardiac myosin light chain-1 (cMLC1)) and improved cardiac function (ejection fraction (EF) and end diastolic left ventricular inner dimension (LVID)). Apigenin also alleviated endotoxin-induced myocardial injury by modulating oxidative stress (nitrotyrosine and protein carbonyl) and inflammatory cytokines (TNF-α, IL-1β, MIP-1α, and MIP-2) along with their master regulator NFκB. Apigenin modulated redox homeostasis, and its anti-inflammatory role might be associated with its ability to control autophagy. Autophagy (determined by LAMP1, ATG5, and p62), its transcriptional regulator transcription factor EB (TFEB), and downstream target genes including vacuolar protein sorting-associated protein 11 (Vps11) and microtubule-associated proteins 1A/1B light chain 3B (Map1lc3) were modulated by apigenin. Thus, our study demonstrated that apigenin may lead to potential development of new target in sepsis treatment or other myocardial oxidative and/or inflammation-induced injuries. PMID:28828145

Apigenin Alleviates Endotoxin-Induced Myocardial Toxicity by Modulating Inflammation, Oxidative Stress, and Autophagy.

PubMed

Li, Fang; Lang, Fangfang; Zhang, Huilin; Xu, Liangdong; Wang, Yidan; Zhai, Chunxiao; Hao, Enkui

2017-01-01

Apigenin, a component in daily diets, demonstrates antioxidant and anti-inflammatory properties. Here, we intended to explore the mechanism of apigenin-mediated endotoxin-induced myocardial injury and its role in the interplay among inflammation, oxidative stress, and autophagy. In our lipopolysaccharide- (LPS-) induced myocardial injury model, apigenin ameliorated cardiac injury (lactate dehydrogenase (LDH) and creatine kinase (CK)), cell death (TUNEL staining, DNA fragmentation, and PARP activity), and tissue damage (cardiac troponin I (cTnI) and cardiac myosin light chain-1 (cMLC1)) and improved cardiac function (ejection fraction (EF) and end diastolic left ventricular inner dimension (LVID)). Apigenin also alleviated endotoxin-induced myocardial injury by modulating oxidative stress (nitrotyrosine and protein carbonyl) and inflammatory cytokines (TNF- α , IL-1 β , MIP-1 α , and MIP-2) along with their master regulator NF κ B. Apigenin modulated redox homeostasis, and its anti-inflammatory role might be associated with its ability to control autophagy. Autophagy (determined by LAMP1, ATG5, and p62), its transcriptional regulator transcription factor EB (TFEB), and downstream target genes including vacuolar protein sorting-associated protein 11 (Vps11) and microtubule-associated proteins 1A/1B light chain 3B (Map1lc3) were modulated by apigenin. Thus, our study demonstrated that apigenin may lead to potential development of new target in sepsis treatment or other myocardial oxidative and/or inflammation-induced injuries.

Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia

PubMed Central

Ma, Qing; Cornelli, Umberto; Hanin, Israel; Jeske, Walter P.; Linhardt, Robert J.; Walenga, Jeanine M.; Fareed, Jawed; Lee, John M.

2014-01-01

Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer’s type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit anti-inflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents. PMID:17504153

Modulation of lipopolysaccharide-induced chorioamnionitis in fetal sheep by maternal betamethasone.

PubMed

Wolfe, Katherine B; Snyder, Candice C; Gisslen, Tate; Kemp, Matthew W; Newnham, John P; Kramer, Boris W; Jobe, Alan H; Kallapur, Suhas

2013-12-01

We tested the hypothesis that the order of exposure to maternal betamethasone and intra-amniotic (IA) lipopolysaccharide (LPS) will differentially modulate inflammation in the chorioamnion. Time-mated Merino ewes with singleton fetuses received saline alone, IA LPS alone, maternal betamethasone before LPS, or betamethasone after LPS. We assessed inflammatory markers in the chorioamnion and the amniotic fluid. Inflammatory cell infiltration, expression of myeloperoxidase, serum amyloid A3 (acute phase reactant) in the chorioamnion, and levels of interleukin (IL)-8 in the amniotic fluid increased 7 days after LPS exposure. Betamethasone prior to LPS decreased infiltration of the inflammatory cells, CD3+ T cells, and decreased the levels of IL-1β and IL-8 in the amniotic fluid. Betamethasone 7 days prior to LPS exposure suppressed LPS-induced inflammation. The markers of inflammation largely had returned to the baseline 14 days after LPS exposure.

[Menstruation, inflammation and comorbidities: implications for woman health].

PubMed

Graziottin, A; Zanello, P P

2015-02-01

Menstruation is the genital sign of systemic endocrine events. Heterogeneity of perimenstrual symptoms is associated with levels of inflammation, triggered by the fall of estrogens at genital and systemic level. Aim of the review is to concisely analyze the evidence on: 1) genital and systemic endocrine and inflammatory events associated with periods and perimenstrual symptoms; 2) rationale of intervention to reduce their intensity and impact on women's lives. This review of the literature, selected with a clinical perspective, supports the inflammatory basis of the menstrual event, triggered by the estrogens' and progesterone' fall. Moreover, the review analyzes the endocrine and inflammatory basis of perimenstrual pelvic and extrapelvic symptoms such as: menstrual pain, menstrual irregularities, premenstrual syndrome, gastrointestinal symptoms, catamenial headache, depression, perimenstrual myalgia, joint pain, allergies and asthma, heavy menstrual bleeding, associated ironless anemia, brain and behavioral consequences. Inflammation, with increase of cytokines and other markers, is modulated by the degranulation of mast cells at the basal level of the endometrium, in the blood, in all the organs where mast-cell are already activated from local pathologies and within the brain. The shift of inflammation from physiological to a pathologic intensity increases the severity of perimenstrual symptoms. Symptoms persist, moderately attenuated, also during the hormone free interval (HFI) in contraception. The HFI reduction from seven to two days significantly reduces menstrual inflammation and associated symptoms.

Inflammatory bowel disease: cause and immunobiology.

PubMed

Baumgart, Daniel C; Carding, Simon R

2007-05-12

Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.

Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis

PubMed Central

Pastores, S

2003-01-01

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial. PMID:12566544

Chitosan-triclosan particles modulate inflammatory signaling in gingival fibroblasts.

PubMed

Pavez, L; Tobar, N; Chacón, C; Arancibia, R; Martínez, C; Tapia, C; Pastor, A; González, M; Martínez, J; Smith, P C

2018-04-01

An important goal of periodontal therapy is the modulation of the inflammatory response. To this end, several pharmacological agents have been evaluated. Triclosan corresponds to an antibacterial and anti-inflammatory agent currently used in periodontal therapy. Chitosan is a natural polymer that may act as a drug delivery agent and exerts antibacterial and anti-inflammatory activities. Therefore, an association between both molecules might be useful to prevent inflammation and tissue destruction in periodontal tissues. In the present study, we have generated chitosan-triclosan particles and evaluated their morphology, charge, biocompatibility and gene expression analysis in human gingival fibroblasts. The chitosan-triclosan particles size and Z potential were 129 ± 47 nm and 51 ± 17 mV respectively. Human gingival fibroblast viability was not affected by chitosan-triclosan. A total of 1533 genes were upregulated by interleukin (IL)-1β. On the other hand, 943 were downregulated in fibroblasts stimulated with IL-1β plus chitosan-triclosan particles. Fifty-one genes were identified as molecular targets upregulated by IL-1 β and downregulated by the chitosan-triclosan particles. The gene ontology analysis revealed that these genes were enriched in categories related to biological processes, molecular function and cellular components. Furthermore, using real-time reverse transcription-polymerase chain reaction beta-actin, fibronectin, interleukin-6 and IL-1b genes were confirmed as targets upregulated by IL-1β and downregulated by chitosan-triclosan particles. Our results show that chitosan-triclosan particles are able to modulate the inflammatory response in gingival fibroblasts. This effect might be useful in the prevention and/or treatment of inflammation in periodontal diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anti-inflammatory activity of p-coumaryl alcohol-γ-O-methyl ether is mediated through modulation of interferon-γ production in Th cells

PubMed Central

Yu, E-S; Min, H-J; Lee, K; Lee, M-S; Nam, J-W; Seo, E-K; Hong, J-H; Hwang, E-S

2009-01-01

Background and purpose: p-Coumaryl alcohol-γ-O-methyl ether (CAME) was isolated from Alpinia galanga and shown to contain a phenylpropanoid structure similar to p-coumaryl diacetate (CDA). CDA is known to have antioxidant and anti-inflammatory activity, but the biochemical activities of CAME are unknown. Inflammation is mediated by inflammatory cytokine production, in particular, by CD4+ T helper cells (Th cells), but it is unclear whether phenylpropanoids affect cytokine production in Th cells. In this study, we decided to investigate the functions of CAME and CDA in CD4+ Th cells. Experimental approach: Mouse CD4+ Th cells were isolated from C57BL6 mice and stimulated with an antibody against T cell receptors in the presence of phenylpropanoids. Cytokine production was measured by elisa and intracellular cytokine staining. Gene knockout mice and tetracycline-inducible transgenic mice were used to examine the molecular mechanisms of phenylpropanoids on modulation of cytokine production. Key results: CAME potently reduced intracellular reactive oxygen species in Th cells, as does CDA. However, although CDA was cytotoxic, CAME selectively and potently suppresses interferon-γ (IFNγ) production in CD4+ Th cells, without toxicity. This effect was caused by attenuated expression of the transcription factor, T-box protein expressed in T cells (T-bet), and T-bet was essential for CAME to inhibit IFNγ production in CD4+ Th cells. Conclusions and implications: CAME selectively and substantially suppresses IFNγ production in CD4+ Th cells by decreasing T-bet expression. As increased IFNγ production by CD4+ Th cells can mediate inflammatory immune responses, a selective IFNγ suppressor, such as CAME may be an effective, naturally occurring, compound for modulating inflammatory immune disorders. PMID:19226286

Short term supplementation of dietary antioxidants selectively regulates the inflammatory responses during early cutaneous wound healing in diabetic mice

PubMed Central

2011-01-01

Background Diabetic foot ulcers are serious complications for diabetic patients, yet the precise mechanism that underlines the treatment of these diabetic complications remains unclear. We hypothesized that dietary antioxidant supplementation with vitamin C, combined either with vitamin E or with vitamin E and NAC, improves delayed wound healing through modulation of blood glucose levels, oxidative stress, and inflammatory response. Methods Diabetes was induced by administration of alloxan monohydrate. Mice were divided into 4 groups; CON (non-diabetic control mice fed AIN 93 G purified rodent diet), DM (diabetic mice fed AIN 93 G purified rodent diet), VCE (diabetic mice fed 0.5% vitamin C and 0.5% vitamin E supplemented diet), and Comb (diabetic mice fed 0.5% vitamin C, 0.5% vitamin E, and 2.5% NAC supplemented diet). After 10 days of dietary antioxidant supplementation, cutaneous full-thickness excisional wounds were performed, and the rate of wound closure was examined. TBARS as lipid peroxidation products and vitamin E levels were measured in the liver. Expression levels of oxidative stress and inflammatory response related proteins were measured in the cutaneous wound site. Results Dietary antioxidant supplementation improved blood glucose levels and wound closure rate and increased liver vitamin E, but not liver TBARS levels in the diabetic mice as compared to those of the CON. In addition, dietary antioxidant supplementation modulated the expression levels of pIκBα, HO-1, CuZnSOD, iNOS and COX-2 proteins in the diabetic mice. Conclusions These findings demonstrated that delayed wound healing is associated with an inflammatory response induced by hyperglycaemia, and suggests that dietary antioxidant supplementation may have beneficial effects on wound healing through selective modulation of blood glucose levels, oxidative stress, and inflammatory response. PMID:22088091

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.

Ion channels in inflammation.

PubMed

Eisenhut, Michael; Wallace, Helen

2011-04-01

Most physical illness in vertebrates involves inflammation. Inflammation causes disease by fluid shifts across cell membranes and cell layers, changes in muscle function and generation of pain. These disease processes can be explained by changes in numbers or function of ion channels. Changes in ion channels have been detected in diarrhoeal illnesses, pyelonephritis, allergy, acute lung injury and systemic inflammatory response syndromes involving septic shock. The key role played by changes in ion transport is directly evident in inflammation-induced pain. Expression or function of all major categories of ion channels like sodium, chloride, calcium, potassium, transient receptor potential, purinergic receptor and acid-sensing ion channels can be influenced by cyto- and chemokines, prostaglandins, leukotrienes, histamine, ATP, reactive oxygen species and protons released in inflammation. Key pathways in this interaction are cyclic nucleotide, phosphoinositide and mitogen-activated protein kinase-mediated signalling, direct modification by reactive oxygen species like nitric oxide, ATP or protons and disruption of the cytoskeleton. Therapeutic interventions to modulate the adverse and overlapping effects of the numerous different inflammatory mediators on each ion transport system need to target adversely affected ion transport systems directly and locally.

Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis.

PubMed

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Mörgelin, Matthias; van der Plas, Mariena J A; Rydengård, Victoria; Malmsten, Martin; Albiger, Barbara; Schmidtchen, Artur

2012-01-01

Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis.

Modulation of Cellular Stress Response via the Erythropoietin/CD131 Heteroreceptor Complex in Mouse Mesenchymal-Derived Cells

PubMed Central

Bohr, Stefan; Patel, Suraj J; Vasko, Radovan; Shen, Keyue; Iracheta-Vellve, Arvin; Lee, Jungwoo; Bale, Shyam Sundhar; Chakraborty, Nilay; Brines, Michael; Cerami, Anthony; Berthiaume, Francois; Yarmush, Martin L

2014-01-01

Tissue protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO-signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO-signaling in defined cell populations. In this study we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO-signaling strongly modulated transcriptional, translational or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1) and activator protein 1 (AP1). We conclude that alternative EPO-signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis. PMID:25373867

Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.

PubMed

Wanngren, Johanna; Ottervald, Jan; Parpal, Santiago; Portelius, Erik; Strömberg, Kia; Borgegård, Tomas; Klintenberg, Rebecka; Juréus, Anders; Blomqvist, Jenny; Blennow, Kaj; Zetterberg, Henrik; Lundkvist, Johan; Rosqvist, Susanne; Karlström, Helena

2012-09-21

The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.

Modulation of Human Immune Response by Fungal Biocontrol Agents

PubMed Central

Konstantinovas, Cibele; de Oliveira Mendes, Tiago A.; Vannier-Santos, Marcos A.; Lima-Santos, Jane

2017-01-01

Although the vast majority of biological control agents is generally regarded as safe for humans and environment, the increased exposure of agriculture workers, and consumer population to fungal substances may affect the immune system. Those compounds may be associated with both intense stimulation, resulting in IgE-mediated allergy and immune downmodulation induced by molecules such as cyclosporin A and mycotoxins. This review discusses the potential effects of biocontrol fungal components on human immune responses, possibly associated to infectious, inflammatory diseases, and defective defenses. PMID:28217107

Human Properdin Opsonizes Nanoparticles and Triggers a Potent Pro-inflammatory Response by Macrophages without Involving Complement Activation

PubMed Central

Kouser, Lubna; Paudyal, Basudev; Kaur, Anuvinder; Stenbeck, Gudrun; Jones, Lucy A.; Abozaid, Suhair M.; Stover, Cordula M.; Flahaut, Emmanuel; Sim, Robert B.; Kishore, Uday

2018-01-01

Development of nanoparticles as tissue-specific drug delivery platforms can be considerably influenced by the complement system because of their inherent pro-inflammatory and tumorigenic consequences. The complement activation pathways, and its recognition subcomponents, can modulate clearance of the nanoparticles and subsequent inflammatory response and thus alter the intended translational applications. Here, we report, for the first time, that human properdin, an upregulator of the complement alternative pathway, can opsonize functionalized carbon nanotubes (CNTs) via its thrombospondin type I repeat (TSR) 4 and 5. Binding of properdin and TSR4+5 is likely to involve charge pattern/polarity recognition of the CNT surface since both carboxymethyl cellulose-coated carbon nanotubes (CMC-CNT) and oxidized (Ox-CNT) bound these proteins well. Properdin enhanced the uptake of CMC-CNTs by a macrophage cell line, THP-1, mounting a robust pro-inflammatory immune response, as revealed by qRT-PCR, multiplex cytokine array, and NF-κB nuclear translocation analyses. Properdin can be locally synthesized by immune cells in an inflammatory microenvironment, and thus, its interaction with nanoparticles is of considerable importance. In addition, recombinant TSR4+5 coated on the CMC-CNTs inhibited complement consumption by CMC-CNTs, suggesting that nanoparticle decoration with TSR4+5, can be potentially used as a complement inhibitor in a number of pathological contexts arising due to exaggerated complement activation. PMID:29483907

Contact lens wear is intrinsically inflammatory.

PubMed

Efron, Nathan

2017-01-01

Eye-care practitioners typically associate ocular inflammation during contact lens wear with serious complications such as microbial keratitis; however, more subtle mechanisms may be at play. This paper tests the notion that contact lens wear is intrinsically inflammatory by exploring whether uncomplicated contact lens wear meets the classical, clinical definition of inflammation - rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function) - as well as the contemporary, sub-clinical definition of inflammation (cellular and biochemical reactions). It is demonstrated that all of these clinical and sub-clinical criteria are met with hydrogel lens wear and most are met with silicone hydrogel lens wear, indicating that uncomplicated contact lens wear is intrinsically inflammatory. Consideration of both traditional and contemporary thinking about the role of inflammation in the human body leads to the perhaps surprising conclusion that the chronic, low grade, sub-clinical inflammatory status of the anterior eye during contact lens wear, which may be termed 'para-inflammation', is a positive, protective phenomenon, whereby up-regulation of the immune system, in a non-damaging way, maintains the eye in a state of 'heightened alert', ready to ward off any extrinsic noxious challenge. Characterisation of this inflammatory status may lead to the development of lens engineering or pharmacological strategies to modulate contact lens-induced inflammation, so as to render lens wear more safe and comfortable. © 2016 Optometry Australia.

Adiponectin attenuates LPS-induced acute lung injury through suppression of endothelial cell activation1

PubMed Central

Konter, Jason M; Parker, Jennifer L; Baez, Elizabeth; Li, Stephanie Z; Ranscht, Barbara; Denzel, Martin; Little, Frederic F; Nakamura, Kazuto; Ouchi, Noriyuki; Fine, Alan; Walsh, Kenneth; Summer, Ross S

2011-01-01

Adiponectin (APN) is an adipose tissue-derived factor with anti-inflammatory and vascular protective properties whose levels paradoxically decrease with increasing body fat. In this study, APN’s role in the early development of ALI to lipopolysaccharide (LPS) was investigated. Intra-tracheal (i.t.) LPS elicited an exaggerated systemic inflammatory response in APN-deficient (APN−/−) mice compared to wild-type (wt) littermates. Increased lung injury and inflammation were observed in APN−/− mice as early as 4 hours after delivery of LPS. Targeted gene expression profiling performed on immune and endothelial cells isolated from lung digests 4 hours after LPS administration showed increased pro-inflammatory gene expression (e.g. IL-6) only in endothelial cells of APN−/− mice when compared to wt mice. Direct effects on lung endothelium were demonstrated by APN’s ability to inhibit LPS-induced IL-6 production in primary human endothelial cells in culture. Furthermore, T-cadherin-deficient (T-cad−/−) mice that have significantly reduced lung airspace APN but high serum APN levels had pulmonary inflammatory responses after i.t. LPS that were similar to those of wt mice. These findings indicate the importance of serum APN in modulating LPS-induced ALI and suggest that conditions leading to hypoadiponectinemia (e.g. obesity) predispose to development of ALI through exaggerated inflammatory response in pulmonary vascular endothelium. PMID:22156343

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.

Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

PubMed Central

Fried, Nathan T; Maxwell, Christina R; Elliott, Melanie B; Oshinsky, Michael L

2017-01-01

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine. PMID:28457145

Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

PubMed Central

Nagaraja, Sridevi; Reifman, Jaques; Mitrophanov, Alexander Y.

2015-01-01

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation. PMID:26633296

Inhibition of Nod2 Signaling and Target Gene Expression by Curcumin

PubMed Central

Huang, Shurong; Zhao, Ling; Kim, Kihoon; Lee, Dong Seok; Hwang, Daniel H.

2008-01-01

Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn's disease and Blau syndrome. Many phytochemicals possess anti-inflammatory properties. However, it is not known whether any of these phytochemicals might modulate Nod2-mediated immune responses and thus might be of therapeutic value for the intervention of these inflammatory diseases. In this report, we demonstrate that curcumin, a polyphenol found in the plant Curcuma longa, and parthenolide, a sesquiterpene lactone, suppress both ligand-induced and lauric acid-induced Nod2 signaling, leading to the suppression of nuclear factor-κB activation and target gene interleukin-8 expression. We provide molecular and biochemical evidence that the suppression is mediated through the inhibition of Nod2 oligomerization and subsequent inhibition of downstream signaling. These results demonstrate for the first time that curcumin and parthenolide can directly inhibit Nod2-mediated signaling pathways at the receptor level and suggest that Nod2-mediated inflammatory responses can be modulated by these phytochemicals. It remains to be determined whether these phytochemicals possess protective or therapeutic efficacy against Nod2-mediated inflammatory disorders. PMID:18413660

Regulation of Inflammatory Gene Expression in PBMCs by Immunostimulatory Botanicals

PubMed Central

Denzler, Karen L.; Waters, Robert; Jacobs, Bertram L.; Rochon, Yvan; Langland, Jeffrey O.

2010-01-01

Many hundreds of botanicals are used in complementary and alternative medicine for therapeutic use as antimicrobials and immune stimulators. While there exists many centuries of anecdotal evidence and few clinical studies on the activity and efficacy of these botanicals, limited scientific evidence exists on the ability of these botanicals to modulate the immune and inflammatory responses. Using botanogenomics (or herbogenomics), this study provides novel insight into inflammatory genes which are induced in peripheral blood mononuclear cells following treatment with immunomodulatory botanical extracts. These results may suggest putative genes involved in the physiological responses thought to occur following administration of these botanical extracts. Using extracts from immunostimulatory herbs (Astragalus membranaceus, Sambucus cerulea, Andrographis paniculata) and an immunosuppressive herb (Urtica dioica), the data presented supports previous cytokine studies on these herbs as well as identifying additional genes which may be involved in immune cell activation and migration and various inflammatory responses, including wound healing, angiogenesis, and blood pressure modulation. Additionally, we report the presence of lipopolysaccharide in medicinally prepared extracts of these herbs which is theorized to be a natural and active component of the immunostimulatory herbal extracts. The data presented provides a more extensive picture on how these herbs may be mediating their biological effects on the immune and inflammatory responses. PMID:20838436

Extra-virgin olive oil consumption reduces the age-related decrease in HDL and paraoxonase 1 anti-inflammatory activities.

PubMed

Loued, Soumaya; Berrougui, Hicham; Componova, Pamela; Ikhlef, Souad; Helal, Olfa; Khalil, Abdelouahed

2013-10-01

Paraoxonase 1 (PON1) is associated with HDL and modulates the antioxidant and anti-inflammatory role of HDL. The goals of the present study were to investigate the effect of ageing and the role of PON1 on the anti-inflammatory activity of HDL, and to determine whether extra-virgin olive oil (EVOO) consumption could improve the atheroprotective activity of HDL. HDL and PON1 were isolated from the plasma of ten young (Y-HDL and Y-PON1) and ten elderly (E-HDL and E-PON1) healthy volunteers before and after 12 weeks of EVOO consumption. Inflammation was assessed by measuring intracellular adhesion molecule 1 (ICAM-1) expression. THP-1 (human acute monocytic leukaemia cell line) monocyte chemotaxis was measured using a Boyden chamber. Oxidative damage to HDL was assessed by measuring conjugated diene formation and changes in electrophoretic migration. Y-HDL had more anti-inflammatory activity than E-HDL. The conjugated diene content and the electrophoretic mobility of E-HDL were higher than those of Y-HDL. Y-PON1 had significant anti-inflammatory activity, reducing ICAM-1 expression by 32·64 (SD 2·63)%, while E-PON1 had no significant effect. THP-1 chemotaxis measurements confirmed the ICAM-1 expression results. The 12 weeks of EVOO consumption significantly increased the anti-inflammatory activities of both HDL and PON1. The anti-inflammatory activity of HDL was modulated by PON1 and was lower in the elderly volunteers. EVOO consumption increased the anti-inflammatory effect of HDL and reduced the age-related decrease in anti-atherogenic activity.

Lactic acid bacteria and bifidobacteria attenuate the proinflammatory response in intestinal epithelial cells induced by Salmonella enterica serovar Typhimurium.

PubMed

Carey, Christine M; Kostrzynska, Magdalena

2013-01-01

Inflammation is a physiological response to infections and tissue injury; however, abnormal immune responses can give rise to chronic inflammation and contribute to disease progression. Various dietary components, including probiotic lactic acid bacteria and prebiotics, have the potential to modulate intestinal inflammatory responses. One factor in particular, the chemokine interleukin-8 (IL-8, CXCL-8), is one of the major mediators of the inflammatory response. The purpose of this study was to investigate modulation of the inflammatory host response induced by Salmonella enterica serovar Typhimurium DT104 in the presence of selected probiotics and lactic acid bacteria (LAB) isolated from human sources, dairy products, and farm animals. IL-8 gene expression and protein production in HT-29 cells were evaluated by real-time PCR and ELISA, respectively. Pre-incubation of HT-29 cells with Lactobacillus kefir IM002, Bifidobacterium adolescentis FRP 61, Bifidobacterium longum FRP 68 and FRP 69, Bifidobacterium breve FRP 334, and Leuconostoc mesenteroides IM080 significantly inhibited IL-8 secretion induced by Salmonella Typhimurium DT104. Co-culture of selected probiotics and Salmonella Typhimurium DT104 reduced IL-8 production, while potential probiotics and LAB had no effect on IL-8 secretion in HT-29 cells preincubated with Salmonella Typhimurium DT104 prior to adding probiotics. Lactobacillus kefir IM002 supernatant also significantly reduced IL-8 production. In conclusion, our study suggests that probiotic bifidobacteria and LAB modulate cytokine induction and possess anti-inflammatory properties; however, the effectiveness is strain dependent.

Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.

PubMed

Butovsky, Oleg; Siddiqui, Shafiuddin; Gabriely, Galina; Lanser, Amanda J; Dake, Ben; Murugaiyan, Gopal; Doykan, Camille E; Wu, Pauline M; Gali, Reddy R; Iyer, Lakshmanan K; Lawson, Robert; Berry, James; Krichevsky, Anna M; Cudkowicz, Merit E; Weiner, Howard L

2012-09-01

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.

Citral and eugenol modulate DNA damage and pro-inflammatory mediator genes in murine peritoneal macrophages.

PubMed

Porto, Marilia de Paula; da Silva, Glenda Nicioli; Luperini, Bruno Cesar Ottoboni; Bachiega, Tatiana Fernanda; de Castro Marcondes, João Paulo; Sforcin, José Maurício; Salvadori, Daisy Maria Fávero

2014-11-01

Citral and eugenol have been broadly studied because of their anti-inflammatory, antioxidant and antiparasitic potentials. In this study, the effects of citral (25, 50 and 100 µg/mL) and eugenol (0.31, 0.62, 1.24 and 2.48 µg/mL) on the expression (RT-PCR) of the pro-inflammatory mediator genes NF-κB1, COX-2 and TNF-α were evaluated in mouse peritoneal macrophages with or without activation by a bacterial lipopolysaccharide (LPS). Additionally, the genotoxic potentials of two compounds and their capacities to modulate the DNA damage induced by doxorubicin (DXR) were investigated using the comet assay. The data revealed that neither citral nor eugenol changed COX-2, NF-κB1 or TNF-α expression in resting macrophages. However, in LPS-activated cells, citral induced the hypoexpression of COX-2 (100 µg/mL) and TNF-α (50 and 100 µg/mL). Hypoexpression of TNF-α was also detected after cellular exposure to eugenol at the highest concentration (2.48 µg/mL). Both compounds exhibited genotoxic potential (citral at 50 and 100 µg/mL and eugenol at all concentrations) but also showed chemopreventive effects, in various treatment protocols. Both citral and eugenol might modulate inflammatory processes and DXR-induced DNA damage, but the use of these compounds must be viewed with caution because they are also able to induce primary DNA lesions.

Butyric acid stimulates bovine neutrophil functions and potentiates the effect of platelet activating factor.

PubMed

Carretta, M D; Hidalgo, A I; Burgos, J; Opazo, L; Castro, L; Hidalgo, M A; Figueroa, C D; Taubert, A; Hermosilla, C; Burgos, R A

2016-08-01

Increased short-chain fatty acid (SCFA) production is associated with subacute ruminal acidosis (SARA) and activation of inflammatory processes. In humans and rodents, SCFAs modulate inflammatory responses in the gut via free fatty acid receptor 2 (FFA2). In bovines, butyric acid is one of the most potent FFA2 agonists. Its expression in bovine neutrophils has recently been demonstrated, suggesting a role in innate immune response in cattle. This study aimed to evaluate if butyric acid modulates oxidative and non-oxidative functions or if it can potentiate other inflammatory mediators in bovine neutrophils. Our results showed that butyric acid can activate bovine neutrophils, inducing calcium (Ca(2+)) influx and mitogen-activated protein kinase (MAPK) phosphorylation, two second messengers involved in FFA2 activation. Ca(2+) influx induced by butyric acid was dependent on the extracellular and intracellular Ca(2+) source and phospholipase C (PLC) activation. Butyric acid alone had no significant effect on reactive oxygen species (ROS) production and chemotaxis; however, a priming effect on platelet-activating factor (PAF), a potent inflammatory mediator, was observed. Butyric acid increased CD63 expression and induced the release of neutrophil granule markers matrix metalloproteinase-9 (MMP-9) and lactoferrin. Finally, we observed that butyric acid induced neutrophil extracellular trap (NET) formation without affecting cellular viability. These findings suggest that butyric acid, a component of the ruminal fermentative process, can modulate the innate immune response of ruminants. Copyright © 2016 Elsevier B.V. All rights reserved.

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

PubMed Central

Wang, Xiao-Min; Wu, Tian-Xia; Hamza, May; Ramsay, Edward S.; Wahl, Sharon M.; Dionne, Raymond A.

2007-01-01

New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A2 and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the pro-inflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2. PMID:17070997

Expression and arrangement of extracellular matrix proteins in the lungs of mice infected with Paracoccidioides brasiliensis conidia

PubMed Central

González, Angel; Lenzi, Henrique Leonel; Motta, Ester Maria; Caputo, Luzia; Restrepo, Angela; Cano, Luz Elena

2008-01-01

Extracellular matrix (ECM) proteins are important modulators of migration, differentiation and proliferation for the various cell types present in the lungs; they influence the immune response as well as participate in the adherence of several fungi including Paracoccidioides brasiliensis. The expression, deposition and arrangement of ECM proteins such as laminin, fibronectin, fibrinogen, collagen and proteoglycans in the lungs of mice infected with P. brasiliensis conidia has been evaluated in this study, together with the elastic fibre system. Lungs of BALB/c mice infected with P. brasiliensis conidia were analysed for the different ECM proteins by histological and immunohistochemical procedures at different times of infection. In addition, laser scanning confocal microscopy and scanning electron microscopy were used. During the early periods, the lungs of infected animals showed an inflammatory infiltrate composed mainly of polymorphonuclear neutrophils (PMNs) and macrophages, while during the later periods, mice presented a chronic inflammatory response with granuloma formation. Re-arrangement and increased expression of all ECM proteins tested were observed throughout all studied periods, especially during the occurrence of inflammatory infiltration and formation of the granuloma. The elastic fibre system showed an elastolysis process in all experiments. In conclusion, this study provides new details of pulmonary ECM distribution during the course of paracoccidioidomycosis. PMID:18336528

The emerging role of the endocannabinoid system in cardiovascular disease

PubMed Central

2009-01-01

Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB1 and CB2. Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB1 receptors. Furthermore, tonic activation of CB1 receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB2 receptors in immune cells exerts various immunomodulatory effects, and the CB2 receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders. PMID:19357846

Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity

USDA-ARS?s Scientific Manuscript database

Obesity is associated with a chronic low grade inflammation characterized by high level of pro-inflammatory cytokines and mediators implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been shown to modulate immune-based pathol...

Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis

EPA Science Inventory

Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of inflammation by PM-associated soluble metal, we investigated intracellular solubility of radiolabelled iron oxide (⁵⁹

Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats

PubMed Central

Kan, Min Hui; Yang, Ting; Fu, Hui Qun; Fan, Long; Wu, Yan; Terrando, Niccolò; Wang, Tian-Long

2016-01-01

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1β expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure. PMID:27493629

Functional Foods for Health: The Interrelated Antioxidant and Anti-Inflammatory Role of Fruits, Vegetables, Herbs, Spices and Cocoa in Humans

PubMed Central

Serafini, Mauro; Peluso, Ilaria

2016-01-01

The health benefits of plant food-based diets could be related to both integrated antioxidant and anti-inflammatory mechanisms exerted by a wide array of phytochemicals present in fruit, vegetables, herbs and spices. Therefore, there is mounting interest in identifying foods, food extracts and phytochemical formulations from plant sources which are able to efficiently modulate oxidative and inflammatory stress to prevent diet-related diseases. This paper reviews available evidence about the effect of supplementation with selected fruits, vegetables, herbs, spices and their extracts or galenic formulation on combined markers of redox and inflammatory status in humans. PMID:27881064

Computational modeling of heterogeneity and function of CD4+ T cells

PubMed Central

Carbo, Adria; Hontecillas, Raquel; Andrew, Tricity; Eden, Kristin; Mei, Yongguo; Hoops, Stefan; Bassaganya-Riera, Josep

2014-01-01

The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation. PMID:25364738

The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

PubMed

Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

2016-09-01

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy

PubMed Central

Wert, Katherine J; Mahajan, Vinit B; Zhang, Lijuan; Yan, Yuanqing; Li, Yao; Tosi, Joaquin; Wei Hsu, Chun; Nagasaki, Takayuki; Janisch, Kerstin M; Grant, Maria B; Mahajan, MaryAnn; Bassuk, Alexander G; Tsang, Stephen H

2016-01-01

Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders. PMID:27195131

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

PubMed Central

Abraham, Clara; Dulai, Parambir S.; Vermeire, Séverine; Sandborn, William J.

2016-01-01

Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID:27780712

The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer

PubMed Central

2011-01-01

The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status. PMID:21418564

What are the local and systemic biologic reactions and mediators to wear debris, and what host factors determine or modulate the biologic response to wear particles?

PubMed

Tuan, Rocky S; Lee, Francis Young-In; T Konttinen, Yrjö; Wilkinson, J Mark; Smith, Robert Lane

2008-01-01

New clinical and basic science data on the cellular and molecular mechanisms by which wear particles stimulate the host inflammatory response have provided deeper insight into the pathophysiology of periprosthetic bone loss. Interactions among wear particles, macrophages, osteoblasts, bone marrow-derived mesenchymal stem cells, fibroblasts, endothelial cells, and T cells contribute to the production of pro-inflammatory and pro-osteoclastogenic cytokines such as TNF-alpha, RANKL, M-SCF, PGE2, IL-1, IL-6, and IL-8. These cytokines not only promote osteoclastogenesis but interfere with osteogenesis led by osteoprogenitor cells. Recent studies indicate that genetic variations in TNF-alpha, IL-1, and FRZB can result in subtle changes in gene function, giving rise to altered susceptibility or severity for periprosthetic inflammation and bone loss. Continuing research on the biologic effects and mechanisms of action of wear particles will provide a rational basis for the development of novel and effective ways of diagnosis, prevention, and treatment of periprosthetic inflammatory bone loss.

Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis.

PubMed

Zhou, Kai; Zhong, Qi; Wang, Yan-Chun; Xiong, Xiao-Yi; Meng, Zhao-You; Zhao, Ting; Zhu, Wen-Yao; Liao, Mao-Fan; Wu, Li-Rong; Yang, Yuan-Rui; Liu, Juan; Duan, Chun-Mei; Li, Jie; Gong, Qiu-Wen; Liu, Liang; Yang, Mei-Hua; Xiong, Ao; Wang, Jian; Yang, Qing-Wu

2017-03-01

Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3 DTR -mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3β), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-β did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3β/PTEN axis.

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.

Sphingosine-1-Phosphate Signaling in Inflammatory Bowel Disease.

PubMed

Nielsen, Ole Haagen; Li, Yuan; Johansson-Lindbom, Bengt; Coskun, Mehmet

2017-04-01

An unmet medical need exists for the development of targeted therapies for the treatment of inflammatory bowel disease (IBD) with easily administered and stable oral drugs, particularly as most patients on biologics [i.e., tumor necrosis factor (TNF) inhibitors and anti-integrins] are either primary non-responders or lose responsiveness during maintenance treatment. A new class of small molecules, sphingosine-1-phosphate (S1P) receptor modulators, has recently shown efficacy in IBD. Here we provide an overview of the mechanism of action of this novel treatment principle in the context of intestinal inflammation. The remarkable impact of therapeutic modulation of the S1P/S1P receptor axis reflects the complexity of the pathogenesis of IBD and the fact that S1P receptor modulation may be a logical therapeutic approach for the future management of IBD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

PubMed

Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

2015-12-15

Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone. Copyright © 2015 Elsevier B.V. All rights reserved.

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

PubMed Central

Nwachukwu, Jerome C; Srinivasan, Sathish; Bruno, Nelson E; Parent, Alexander A; Hughes, Travis S; Pollock, Julie A; Gjyshi, Olsi; Cavett, Valerie; Nowak, Jason; Garcia-Ordonez, Ruben D; Houtman, René; Griffin, Patrick R; Kojetin, Douglas J; Katzenellenbogen, John A; Conkright, Michael D; Nettles, Kendall W

2014-01-01

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity. DOI: http://dx.doi.org/10.7554/eLife.02057.001 PMID:24771768

White matter hyperintensities, systemic inflammation, brain growth, and cognitive functions in children exposed to air pollution.

PubMed

Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Styner, Martin; Gómez-Garza, Gilberto; Zhu, Hongtu; Torres-Jardón, Ricardo; Carlos, Esperanza; Solorio-López, Edelmira; Medina-Cortina, Humberto; Kavanaugh, Michael; D'Angiulli, Amedeo

2012-01-01

Air pollution exposures are linked to neuroinflammation and neuropathology in young urbanites. Forty percent of exposed children and young adults exhibit frontal tau hyperphosphorylation and 51% have amyloid-β diffuse plaques compared to 0% in low pollution controls. In older adults, white matter hyperintensities (WMH) are associated with cognitive deficits while inflammatory markers correlate with greater atrophy than expected for age. We investigated patterns of WMH, magnetic resonance imaging (MRI) volume growth, blood inflammatory mediators, and cognition in matched children from two urban cohorts: one severely and one minimally exposed to air pollution. Baseline and one year follow-up measurements of cognitive abilities, brain MRI volumes, and blood were collected in 20 Mexico City (MC) children (10 with WMH+, and 10 without WMH-) and 10 matched controls (WMH-). MC WMH- children display the profile of classical pro-inflammatory defensive responses: high interleukin 12, production of powerful pro-inflammatory cytokines, and low concentrations of key cytokines and chemokines associated with neuroprotection. MC WMH+ children exhibit a response involved in resolution of inflammation, immunoregulation, and tissue remodeling. The MC WMH+ group responded to the air pollution-associated brain volumetric alterations with white and grey matter volume increases in temporal, parietal, and frontal regions and better cognitive performance compared to MC WMH-. We conclude that complex modulation of cytokines and chemokines influences children's central nervous system structural and volumetric responses and cognitive correlates resulting from environmental pollution exposures. Identification of biomarkers associating systemic inflammation to brain growth is critical for detecting children at higher risk for cognitive deficits and neurodegeneration, thereby warranting early implementation of neuroprotective measures.

Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.

PubMed

Neyrinck, Audrey M; Alligier, Maud; Memvanga, Patrick B; Névraumont, Elodie; Larondelle, Yvan; Préat, Véronique; Cani, Patrice D; Delzenne, Nathalie M

2013-01-01

Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation.

PubMed

Bergsbaken, Tessa; Cookson, Brad T

2009-11-01

Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses.

Curcuma longa Extract Associated with White Pepper Lessens High Fat Diet-Induced Inflammation in Subcutaneous Adipose Tissue

PubMed Central

Memvanga, Patrick B.; Névraumont, Elodie; Larondelle, Yvan; Préat, Véronique; Cani, Patrice D.; Delzenne, Nathalie M.

2013-01-01

Background Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Methodology/Principal Findings Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. Conclusions/Significance These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition. PMID:24260564

Modulation of Gut Microbiota in the Management of Metabolic Disorders: The Prospects and Challenges

PubMed Central

Erejuwa, Omotayo O.; Sulaiman, Siti A.; Ab Wahab, Mohd S.

2014-01-01

The gut microbiota plays a number of important roles including digestion, metabolism, extraction of nutrients, synthesis of vitamins, prevention against pathogen colonization, and modulation of the immune system. Alterations or changes in composition and biodiversity of the gut microbiota have been associated with many gastrointestinal tract (GIT) disorders such as inflammatory bowel disease and colon cancer. Recent evidence suggests that altered composition and diversity of gut microbiota may play a role in the increased prevalence of metabolic diseases. This review article has two main objectives. First, it underscores approaches (such as probiotics, prebiotics, antimicrobial agents, bariatric surgery, and weight loss strategies) and their prospects in modulating the gut microbiota in the management of metabolic diseases. Second, it highlights some of the current challenges and discusses areas of future research as it relates to the gut microbiota and metabolic diseases. The prospect of modulating the gut microbiota seems promising. However, considering that research investigating the role of gut microbiota in metabolic diseases is still in its infancy, more rigorous and well-designed in vitro, animal and clinical studies are needed. PMID:24608927

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

PubMed

Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

2017-08-01

Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

PubMed Central

Savio, Luiz E. B.; de Andrade Mello, Paola; da Silva, Cleide Gonçalves; Coutinho-Silva, Robson

2018-01-01

Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors—P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases. PMID:29467654

Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases.

PubMed

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco Javier; Vilchez-Padial, Laura Maria; Gil, Angel

2017-05-28

Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response. The present study reviewed the effects of probiotics and synbiotics on intestinal chronic diseases in in vitro, animal, and human studies, particularly in randomized clinical trials. The selected probiotics exhibit in vitro anti-inflammatory properties. Probiotic strains and cell-free supernatants reduced the expression of pro-inflammatory cytokines via action that is principally mediated by toll-like receptors. Probiotic administration improved the clinical symptoms, histological alterations, and mucus production in most of the evaluated animal studies, but some results suggest that caution should be taken when administering these agents in the relapse stages of IBD. In addition, no effects on chronic enteropathies were reported. Probiotic supplementation appears to be potentially well tolerated, effective, and safe in patients with IBD, in both CD and UC. Indeed, probiotics such as Bifidobacterium longum 536 improved the clinical symptoms in patients with mild to moderate active UC. Although it has been proposed that probiotics can provide benefits in certain conditions, the risks and benefits should be carefully assessed before initiating any therapy in patients with IBD. For this reason, further studies are required to understand the precise mechanism by which probiotics and synbiotics affect these diseases.

Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases

PubMed Central

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco Javier; Vilchez-Padial, Laura Maria; Gil, Angel

2017-01-01

Probiotics and synbiotics are used to treat chronic diseases, principally due to their role in immune system modulation and the anti-inflammatory response. The present study reviewed the effects of probiotics and synbiotics on intestinal chronic diseases in in vitro, animal, and human studies, particularly in randomized clinical trials. The selected probiotics exhibit in vitro anti-inflammatory properties. Probiotic strains and cell-free supernatants reduced the expression of pro-inflammatory cytokines via action that is principally mediated by toll-like receptors. Probiotic administration improved the clinical symptoms, histological alterations, and mucus production in most of the evaluated animal studies, but some results suggest that caution should be taken when administering these agents in the relapse stages of IBD. In addition, no effects on chronic enteropathies were reported. Probiotic supplementation appears to be potentially well tolerated, effective, and safe in patients with IBD, in both CD and UC. Indeed, probiotics such as Bifidobacterium longum 536 improved the clinical symptoms in patients with mild to moderate active UC. Although it has been proposed that probiotics can provide benefits in certain conditions, the risks and benefits should be carefully assessed before initiating any therapy in patients with IBD. For this reason, further studies are required to understand the precise mechanism by which probiotics and synbiotics affect these diseases. PMID:28555037

The Representation of Inflammatory Signals in the Brain – A Model for Subjective Fatigue in Multiple Sclerosis

PubMed Central

Hanken, Katrin; Eling, Paul; Hildebrandt, Helmut

2014-01-01

In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may contribute to subjective fatigue in MS patients. Pro-inflammatory cytokines represent primary mediators of immune-to-brain-communication, modulating changes in the neurophysiology of the central nervous system. Recently, we proposed a model arguing that fatigue in MS patients is a subjective feeling, which is related to inflammation. Moreover, it implies that fatigue can be measured behaviorally only by applying specific cognitive tasks related to alertness and vigilance. In the present review, we focus on the subjective feeling of MS-related fatigue. We examine the hypothesis that the subjective feeling of MS-related fatigue may be a variant of inflammation-induced sickness behavior, resulting from cytokine-mediated activity changes within brain areas involved in interoception and homeostasis including the insula, the anterior cingulate, and the hypothalamus. We first present studies demonstrating a relationship between pro-inflammatory cytokines and subjective fatigue in healthy individuals, in people with inflammatory disorders, and particularly in MS patients. Subsequently, we discuss studies analyzing the impact of anti-inflammatory treatment on fatigue. In the next part of this review, we present studies on the transmission and neural representation of inflammatory signals, with a special focus on possible neural concomitants of inflammation-induced fatigue. We also present two of our studies on the relationship between local gray and white matter atrophy and fatigue in MS patients. Finally, we discuss some implications of our findings and future perspectives. PMID:25566171

Does physical exercise reduce excessive daytime sleepiness by improving inflammatory profiles in obstructive sleep apnea patients?

PubMed

Alves, Eduardo da Silva; Ackel-D'Elia, Carolina; Luz, Gabriela Pontes; Cunha, Thays Crosara Abrahão; Carneiro, Gláucia; Tufik, Sergio; Bittencourt, Lia Rita Azeredo; de Mello, Marco Tulio

2013-05-01

Obstructive sleep apnea syndrome (OSAS) is associated with a variety of long-term consequences such as high rates of morbidity and mortality, due to excessive diurnal somnolence as well as cardiovascular and metabolic diseases. Obesity, recurrent episodes of upper airway obstruction, progressive hypoxemia, and sleep fragmentation during sleep cause neural, cardiovascular, and metabolic changes. These changes include activation of peripheral sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, insulin sensitivity, and inflammatory cytokines alterations, which predispose an individual to vascular damage. Previous studies proposed that OSAS modulated the expression and secretion of inflammatory cytokines from fat and other tissues. Independent of obesity, patients with OSAS exhibited elevated levels of C-reactive protein, tumor necrosis factor-α and interleukin-6, which are associated with sleepiness, fatigue, and the development of a variety of metabolic and cardiovascular diseases. OSAS and obesity are strongly associated with each other and share many common pathways that induce chronic inflammation. Previous studies suggested that the protective effect of exercise may be partially attributed to the anti-inflammatory effect of regular exercise, and this effect was observed in obese patients. Although some studies assessed the effects of physical exercise on objective and subjective sleep parameters, the quality of life, and mood in patients with OSAS, no study has evaluated the effects of this treatment on inflammatory profiles. In this review, we cited some studies that directed our opinion to believe that since OSAS causes increased inflammation and has excessive daytime sleepiness as a symptom and being that physical exercise improves inflammatory profiles and possibly OSAS symptoms, it must be that physical exercise improves excessive daytime sleepiness due to its improvement in inflammatory profiles.

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.

Tofacitinib ameliorates murine lupus and its associated vascular dysfunction

PubMed Central

Furumoto, Yasuko; Smith, Carolyne K.; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R.; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L.; Trier, Anna M.; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T.; O'Shea, John J.

2016-01-01

Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. PMID:27429362

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

Characteristics of the antitumor activities in tumor cells and modulation of the inflammatory response in RAW264.7 cells of a novel antimicrobial peptide, chrysophsin-1, from the red sea bream (Chrysophrys major).

PubMed

Hsu, Jung-Chieh; Lin, Li-Ching; Tzen, Jason T C; Chen, Jyh-Yih

2011-05-01

The antimicrobial peptide, chrysophsin-1, exhibits antimicrobial activities with similar efficiencies for both gram-negative and gram-positive bacteria. In this study, we examined the antitumor activity and modulation of the inflammatory response of a synthetic chrysophsin-1 peptide. In vitro results showed that chrysophsin-1 had greater inhibitory effects against human fibrosarcoma (HT-1080), histiocytic lymphoma (U937), and epithelial carcinoma (HeLa) cells. LDH release by HeLa cells was comparable to that of an MTS assay after treatment with 1.5-3 μg/ml chrysophsin-1 for 24h. Under SEM and TEM observations, we found no intact cell membranes after chrysophsin-1 treatment of HeLa cells for 8h. The suggested mechanism of the cytotoxic activity of chrysophsin-1 was disruption of cancer cell membranes. In addition, we also examined caspase-3, -8, and -9 activities by Western blotting; the results excluded the participation of apoptosis in chrysophsin-1's effect on HeLa cells. Stimulation by lipopolysaccharide induced tumor necrosis factor (TNF)-α which was able to modulate chrysophsin-1 treatment of RAW264.7 cells and inhibited endogenous TNF-α release but did not block its secretion. With data from this study, we demonstrate that chrysophsin-1 has antimicrobial and antitumor activities and modulates the inflammatory response in RAW264.7 cells. Copyright © 2011 Elsevier Inc. All rights reserved.

Anti-inflammatory effect of a Nuphar lutea partially purified leaf extract in murine models of septic shock.

PubMed

Ozer, J; Levi, T; Golan-Goldhirsh, A; Gopas, J

2015-02-23

Various plant organs of Nuphar lutea (L.) SM. (Nymphaeaceae) are used in traditional medicine for the treatment of arthritis, fever, aches, pains and inflammation. The main purpose of this study was to determine the anti-inflammatory effect of Nuphar lutea leaf extract (NUP) in two septic shock models: (1) Survival of mice challenged with a lethal dose of LPS, determination of pro-inflammatory and anti-inflammatory cytokines in serum, as well as in peritoneal macrophages in cell culture. (2) The effect of NUP in a murine model of fecal-induced peritonitis. NUP pre-treatment partially protected mice in two models of acute septic shock. We concluded that NUP is anti-inflammatory by inhibiting the NF-κB pathway, modulating cytokine production and ERK phosphorylation. A significant average survival rate (60%) of LPS lethally-challenged mice was achieved by pre-treatment with NUP. In addition, NUP pre-treatment reduced nuclear NF-κB translocation in peritoneal macrophages. The production of pro-inflammatory cytokines, TNF-α, IL-6 and IL-12, in the sera of LPS-treated mice or in the supernatants of peritoneal macrophages stimulated with LPS for 2-6 h was also decreased by NUP. Pre-treatment with NUP caused a significant increase in the anti-inflammatory cytokine IL-10. The NUP pre-treatment reduced and delayed mortality in mice with fecal-induced peritonitis. Our studies also revealed that NUP pre-treatment induced a dose-dependent phosphorylation of ERK in peritoneal macrophages. Since most of the reports about the anti-inflammatory effect of Nuphar lutea refer to rhizome and root powder and extracts, it is important to clarify the effectiveness of leaf extract as a source for such activity. NUP pre-treatment partially protected mice in two models of acute septic shock. We concluded that NUP is anti-inflammatory by inhibiting the NF-κB pathway, modulating cytokine production and ERK phosphorylation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

PubMed Central

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Kallás, Esper Georges; Irigoyen, Maria Cláudia

2016-01-01

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg−1·day−1) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups—denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups—were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3+ cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4+CD25+FOXP3+), and a less extreme decrease in conventional T cells (CD25+FOXP3−) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. PMID:26791829

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

PubMed

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

2016-04-15

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. Copyright © 2016 the American Physiological Society.

Short-term alpha-tocopherol treatment during neonatal period modulates pro-inflammatory response to endotoxin (LPS) challenge in the same calves several months later

USDA-ARS?s Scientific Manuscript database

Vitamin E, a major natural antioxidant, has been previously shown to attenuate pro-inflammatory response to immune challenge in cattle. Our objective was to evaluate the effect of short-term treatment with alpha-tocopherol in newborn calves on selected elements of the pro-inflamatory response to LPS...

Naringin regulates cholesterol homeostasis and inhibits inflammation via modulating NF-κB and ERK signaling pathways in vitro.

PubMed

Liang, Jing; Wang, Changyuan; Peng, Jinyong; Li, Wenshuang; Jin, Yue; Liu, Qi; Meng, Qiang; Liu, Kexin; Sun, Huijun

2016-02-01

The main purpose of this study was to examine if naringin contributed to the regulation of cholesterol homeostasis and inflammatory cytokine expressions in cholesterol and 25-OH-cholesterol-treated HepG2 cells and TNF-α-treated HUVECs. The gene and protein expressions related to cholesterol homeostasis and inflammation were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. We obtained the following results: (1) A concentration-dependent increase of LDLR and CYP7A1 expressions was observed, through activating expressions of SREBP2 and PPARy in HepG2 cells after exposure to naringin; (2) EL gene and protein expressions in HUVECs were inhibited by naringin; (3) the expressions of inflammatory factors such as CRP, TNF-α, ICAM-1 and VCAM-1 in HepG2 cells, ICAM-1 and VCAM-1 in HUVECs restrained by naringin were confirmed; (4) NF-κB and ERK1/2 activities were quenched by naringin. In summary, naringin might not only effectively reduce cholesterol levels by stimulating cholesterol metabolism but also inhibit inflammatory response through reducing inflammatory cytokine expressions. The effects of naringin were achieved via modulating NF-κB and ERK signaling pathways.

Radiation, Inflammation, and Immune Responses in Cancer

PubMed Central

Multhoff, Gabriele; Radons, Jürgen

2012-01-01

Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR. PMID:22675673

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

PubMed Central

Parrish, William R; Rosas-Ballina, Mauricio; Gallowitsch-Puerta, Margot; Ochani, Mahendar; Ochani, Kanta; Yang, Li-Hong; Hudson, LaQueta; Lin, Xinchun; Patel, Nirav; Johnson, Sarah M; Chavan, Sangeeta; Goldstein, Richard S; Czura, Christopher J; Miller, Edmund J; Al-Abed, Yousef; Tracey, Kevin J; Pavlov, Valentin A

2008-01-01

The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1–50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling. PMID:18584048

Deoxynivalenol as a New Factor in the Persistence of Intestinal Inflammatory Diseases: An Emerging Hypothesis through Possible Modulation of Th17-Mediated Response

PubMed Central

Meurens, François; Cognie, Juliette; Abrami, Roberta; Oswald, Isabelle P.; Guzylack-Piriou, Laurence

2013-01-01

Background/Aims Deoxynivalenol (DON) is a mycotoxin produced by Fusarium species which is commonly found in temperate regions worldwide as a natural contaminant of cereals. It is of great concern not only in terms of economic losses but also in terms of animal and public health. The digestive tract is the first and main target of this food contaminant and it represents a major site of immune tolerance. A finely tuned cross-talk between the innate and the adaptive immune systems ensures the homeostatic equilibrium between the mucosal immune system and commensal microorganisms. The aim of this study was to analyze the impact of DON on the intestinal immune response. Methodology Non-transformed intestinal porcine epithelial cells IPEC-1 and porcine jejunal explants were used to investigate the effect of DON on the intestinal immune response and the modulation of naive T cells differentiation. Transcriptomic proteomic and flow cytometry analysis were performed. Results DON induced a pro-inflammatory response with a significant increase of expression of mRNA encoding for IL-8, IL-1α and IL-1β, TNF-α in all used models. Additionally, DON significantly induced the expression of genes involved in the differentiation of Th17 cells (STAT3, IL–17A, IL-6, IL-1β) at the expenses of the pathway of regulatory T cells (Treg) (FoxP3, RALDH1). DON also induced genes related to the pathogenic Th17 cells subset such as IL–23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17) such as TGF-β and IL-10. Conclusion DON triggered multiple immune modulatory effects which could be associated with an increased susceptibility to intestinal inflammatory diseases. PMID:23326479

Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

PubMed

Pappritz, Kathleen; Savvatis, Konstantinos; Miteva, Kapka; Kerim, Bahtiyar; Dong, Fengquan; Fechner, Henry; Müller, Irene; Brandt, Christine; Lopez, Begoña; González, Arantxa; Ravassa, Susana; Klingel, Karin; Diez, Javier; Reinke, Petra; Volk, Hans-Dieter; Van Linthout, Sophie; Tschöpe, Carsten

2018-06-04

Regulatory T (T reg ) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic T reg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic T reg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + T reg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6C high CCR2 high Cx3Cr1 low monocytes and higher retention of proinflammatory Ly6C mid CCR2 high Cx3Cr1 low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + T reg compared with CVB3 + PBS mice. Coculture of T reg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of T reg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6C low CCR2 low Cx3Cr1 high subset. T reg -mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + T reg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + T reg mice compared with CVB3 + PBS mice. In summary, adoptive T reg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

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.

Tributyltin Exposure Alters Cytokine Levels in Mouse Serum

PubMed Central

Lawrence, Shanieek; Pellom, Samuel T.; Shanker, Anil; Whalen, Margaret M.

2016-01-01

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, KC, MIP1β, MIP2 and RANTES was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40, and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in serum of mice exposed to TBT for less than 24 hr. IL1-β, IL-12βp40, IL-5 and IL-15 were also modulated in mouse serum depending on the specific experiment and the exposure concentration. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES, and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines. PMID:27602597

Modulatory in vitro effect of stress hormones on the cytokine response of rainbow trout and gilthead sea bream head kidney stimulated with Vibrio anguillarum bacterin.

PubMed

Khansari, Ali Reza; Parra, David; Reyes-López, Felipe E; Tort, Lluís

2017-11-01

In fish, the stress response and their consequences in the immune system have been widely described. Recently, a differential cytokine regulation between rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) was reported after treatment with stress hormones together with their receptor antagonists. Nevertheless, there is no evidence of whether antagonists for stress hormone receptors may influence the interaction between hormones and cytokines after bacterial administration. Thus, the aim of our study was to evaluate the cytokine expression in the presence of stress hormones (cortisol, ACTH, adrenaline), hormone receptor antagonists and inactivated Vibrio anguillarum bacterin in rainbow trout and gilthead sea bream head kidney primary cell culture (HKPCC). Mifepristone, spironolactone, propranolol and phentolamine were used to block GR, MR, MC2R, and β-/α-adrenoreceptors. Our results showed an expected increase of the pro-inflammatory and anti-inflammatory response after inactivated V. anguillarum bacterin treatment in both species. Cortisol, ACTH and adrenaline did not modulate the expression of immune-related genes in rainbow trout, while in sea bream cortisol was able to reduce the stimulated gene expression of all cytokines. This effect was only restored to basal expression level in IL-1β and TNF-α by mifepristone. ACTH reduced both pro-inflammatory and anti-inflammatory cytokine expression, excluding IL-1β, only in sea bream. Adrenaline enhanced the expression of IL-1β and TGF-β1 stimulated by inactivated V. anguillarum in sea bream, and the effect was diminished by propranolol. In sum, our results confirm that the immunoendocrine differences reported at gene expression profile between two teleost species are also observed after exposure to inactivated V. anguillarum bacterin, suggesting that stress hormones would differentially modulate the immune response against pathogens in teleost species. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64+ cells

PubMed Central

Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M.; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

2015-01-01

Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64+ monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients’ inflamed joints that comprised enhanced numbers of CD64+ cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64+ cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64+ cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions. PMID:26670584

Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

PubMed Central

Ortuño Sahagún, D.; Márquez-Aguirre, A. L.; Quintero-Fabián, S.; López-Roa, R. I.; Rojas-Mayorquín, A. E.

2012-01-01

A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods. PMID:23251142

Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise.

PubMed

Pillon Barcelos, Rômulo; Freire Royes, Luiz Fernando; Gonzalez-Gallego, Javier; Bresciani, Guilherme

2017-02-01

The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.

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.

Treating metabolic syndrome's metaflammation with low level light therapy: preliminary results

NASA Astrophysics Data System (ADS)

Yoshimura, Tania M.; Kato, Ilka T.; Deana, Alessandro M.; Ribeiro, Martha S.

2014-02-01

Metabolic syndrome comprises a constellation of morbidities such as insulin resistance, hyperinsulinemia, atherogenic dyslipidemia, dysglycemia and obesity (especially abdominal). Metabolic alterations are observed in major insulin target organs, increasing the risk of cardiovascular diseases, type-2 diabetes and therefore mortality. Tissue alterations are characterized by immune cells infiltrates (especially activated macrophages). Released inflammatory mediators such as TNF-α induce chronic inflammation in subjects with metabolic syndrome, since inflammatory pathways are activated in the neighboring cells. The intra-abdominal adipose tissue appears to be of particular importance in the onset of the inflammatory state, and strategies contributing to modulate the inflammatory process within this adipose tissue can mitigate the metabolic syndrome consequences. Considering the low level light therapy (LLLT) recognized benefits in inflammatory conditions, we hypothesized this therapeutic approach could promote positive effects in modulating the inflammatory state of metabolic syndrome. That being the scope of this study, male C57BL/6 mice were submitted to a high-fat/high-fructose diet among 8 weeks to induce metabolic syndrome. Animals were then irradiated on the abdominal region during 21 days using an 850 nm LED (6 sessions, 300 seconds per session, 60 mW output power, ~6 J/cm2 fluence, ~19 mW/cm2 fluence rate). Before and during treatment, blood was sampled either from the retroorbital plexus or from tail puncture for glucose, total cholesterol and triglycerides analysis. So far our results indicate no alterations on these metabolic parameters after LLLT. For further investigations, blood was collected for plasma inflammatory cytokine quantification and fresh ex vivo samples of liver and intra-abdominal adipose tissue were harvested for immunohistochemistry purposes.

Treatment in vitro with PPARα and PPARγ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice.

PubMed

Penas, Federico; Mirkin, Gerardo A; Vera, Marcela; Cevey, Ágata; González, Cintia D; Gómez, Marisa I; Sales, María Elena; Goren, Nora B

2015-05-01

Trypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-α, IL-1β and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARγ, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARγ, PPARα is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-β. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation. Copyright © 2015 Elsevier B.V. All rights reserved.

Antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation.

PubMed

Kostyuk, Vladimir A; Potapovich, Alla I; Suhan, Tatyana O; de Luca, Chiara; Korkina, Liudmila G

2011-05-11

Oxidized low-density lipoproteins (oxLDL) play a critical role in the initiation of atherosclerosis through activation of inflammatory signaling. In the present work we investigated the role of antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Significant decrease in intracellular NO level and superoxide overproduction was found in human umbilical vein endothelial cells (HUVEC) treated with oxLDL, but not with LDL. The redox imbalance was prevented by the addition of quercetin or resveratrol. Expression analysis of 14 genes associated with oxidative stress and inflammation revealed oxLDL-mediated up-regulation of genes specifically involved in leukocyte recruitment and adhesion. This up-regulation could be partially avoided by the addition of verbascoside or resveratrol, while treatment with quercetin resulted in a further increase in the expression of these genes. Lipopolysaccharide (LPS)-treated HUVEC were also used for the evaluation of anti-inflammatory potency of plant polyphenols. Significant differences between HUVEC treaded with oxLDL and LPS were found in both the expression pattern of inflammation-related genes and the effects of plant polyphenols on cellular responses. The present data indicate that plant polyphenols may affect vascular inflammation not only as antioxidants but also as modulators of inflammatory redox signaling pathways. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Toll-Like Receptors: New Players in Myocardial Ischemia/Reperfusion Injury

PubMed Central

Ha, Tuanzhu; Liu, Li; Kelley, Jim; Kao, Race; Williams, David

2011-01-01

Abstract Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack. Antioxid. Redox Signal. 15, 1875–1893. PMID:21091074

Anti-Wrinkle and Anti-Inflammatory Effects of Active Garlic Components and the Inhibition of MMPs via NF-κB Signaling

PubMed Central

Kim, So Ra; Jung, Yu Ri; An, Hye Jin; Kim, Dae Hyun; Jang, Eun Ji; Choi, Yeon Ja; Moon, Kyoung Mi; Park, Min Hi; Park, Chan Hum; Chung, Ki Wung; Bae, Ha Ram; Choi, Yung Whan; Kim, Nam Deuk; Chung, Hae Young

2013-01-01

Skin aging is a multisystem degenerative process caused by several factors, such as, UV irradiation, stress, and smoke. Furthermore, wrinkle formation is a striking feature of photoaging and is associated with oxidative stress and inflammatory response. In the present study, we investigated whether caffeic acid, S-allyl cysteine, and uracil, which were isolated from garlic, modulate UVB-induced wrinkle formation and effect the expression of matrix-metalloproteinase (MMP) and NF-κB signaling. The results obtained showed that all three compounds significantly inhibited the degradation of type І procollagen and the expressions of MMPs in vivo and attenuated the histological collagen fiber disorder and oxidative stress in vivo. Furthermore, caffeic acid and S-allyl cysteine were found to decrease oxidative stress and inflammation by modulating the activities of NF-κB and AP-1, and uracil exhibited an indirect anti-oxidant effect by suppressing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions levels and downregulating transcriptional factors. These results suggest that the anti-wrinkle effects of caffeic acid, S-allyl cysteine, and uracil are due to anti-oxidant and/or anti-inflammatory effects. Summarizing, caffeic acid, S-allyl cysteine, and uracil inhibited UVB-induced wrinkle formation by modulating MMP via NF-κB signaling. PMID:24066081

Caspase-12 and the inflammatory response to Yersinia pestis.

PubMed

Ferwerda, Bart; McCall, Matthew B B; de Vries, Maaike C; Hopman, Joost; Maiga, Boubacar; Dolo, Amagana; Doumbo, Ogobara; Daou, Modibo; de Jong, Dirk; Joosten, Leo A B; Tissingh, Rudi A; Reubsaet, Frans A G; Sauerwein, Robert; van der Meer, Jos W M; van der Ven, André J A M; Netea, Mihai G

2009-09-01

Caspase-12 functions as an antiinflammatory enzyme inhibiting caspase-1 and the NOD2/RIP2 pathways. Due to increased susceptibility to sepsis in individuals with functional caspase-12, an early-stop mutation leading to the loss of caspase-12 has replaced the ancient genotype in Eurasia and a significant proportion of individuals from African populations. In African-Americans, it has been shown that caspase-12 inhibits the pro-inflammatory cytokine production. We assessed whether similar mechanisms are present in African individuals, and whether evolutionary pressures due to plague may have led to the present caspase-12 genotype population frequencies. No difference in cytokine induction through the caspase-1 and/or NOD2/RIP2 pathways was observed in two independent African populations, among individuals with either an intact or absent caspase-12. In addition, stimulations with Yersinia pestis and two other species of Yersinia were preformed to investigate whether caspase-12 modulates the inflammatory reaction induced by Yersinia. We found that caspase-12 did not modulate cytokine production induced by Yersinia spp. Our experiments demonstrate for the first time the involvement of the NOD2/RIP2 pathway for recognition of Yersinia. However, caspase-12 does not modulate innate host defense against Y. pestis and alternative explanations for the geographical distribution of caspase-12 should be sought.

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.

The microbiome-gut-brain axis: from bowel to behavior.

PubMed

Cryan, J F; O'Mahony, S M

2011-03-01

The ability of gut microbiota to communicate with the brain and thus modulate behavior is emerging as an exciting concept in health and disease. The enteric microbiota interacts with the host to form essential relationships that govern homeostasis. Despite the unique enteric bacterial fingerprint of each individual, there appears to be a certain balance that confers health benefits. It is, therefore, reasonable to note that a decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease. Therefore, studies focusing on the impact of enteric microbiota on the host and in particular on the central nervous system are essential to our understanding of the influence of this system. Recent studies published in this Journal demonstrate that germ-free mice display alterations in stress-responsivity, central neurochemistry and behavior indicative of a reduction in anxiety in comparison to conventional mice. Such data offer the enticing proposition that specific modulation of the enteric microbiota may be a useful strategy for stress-related disorders and for modulating the co-morbid aspects of gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease. © 2011 Blackwell Publishing Ltd.

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases

PubMed Central

Xu, Joella; Huang, Guannan; Guo, Tai L.

2016-01-01

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases. PMID:29051427

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases.

PubMed

Xu, Joella; Huang, Guannan; Guo, Tai L

2016-09-26

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases.

Inflammaging and Cancer: A Challenge for the Mediterranean Diet

PubMed Central

Ostan, Rita; Lanzarini, Catia; Pini, Elisa; Scurti, Maria; Vianello, Dario; Bertarelli, Claudia; Fabbri, Cristina; Izzi, Massimo; Palmas, Giustina; Biondi, Fiammetta; Martucci, Morena; Bellavista, Elena; Salvioli, Stefano; Capri, Miriam; Franceschi, Claudio; Santoro, Aurelia

2015-01-01

Aging is considered the major risk factor for cancer, one of the most important mortality causes in the western world. Inflammaging, a state of chronic, low-level systemic inflammation, is a pervasive feature of human aging. Chronic inflammation increases cancer risk and affects all cancer stages, triggering the initial genetic mutation or epigenetic mechanism, promoting cancer initiation, progression and metastatic diffusion. Thus, inflammaging is a strong candidate to connect age and cancer. A corollary of this hypothesis is that interventions aiming to decrease inflammaging should protect against cancer, as well as most/all age-related diseases. Epidemiological data are concordant in suggesting that the Mediterranean Diet (MD) decreases the risk of a variety of cancers but the underpinning mechanism(s) is (are) still unclear. Here we review data indicating that the MD (as a whole diet or single bioactive nutrients typical of the MD) modulates multiple interconnected processes involved in carcinogenesis and inflammatory response such as free radical production, NF-κB activation and expression of inflammatory mediators, and the eicosanoids pathway. Particular attention is devoted to the capability of MD to affect the balance between pro- and anti-inflammaging as well as to emerging topics such as maintenance of gut microbiota (GM) homeostasis and epigenetic modulation of oncogenesis through specific microRNAs. PMID:25859884

Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke

PubMed Central

Campos, Francisco; Pérez-Mato, María; Agulla, Jesús; Blanco, Miguel; Barral, David; Almeida, Ángeles; Brea, David; Waeber, Christian; Castillo, José; Ramos-Cabrer, Pedro

2012-01-01

Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke. PMID:22952923

Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer.

PubMed

Macha, Muzafar A; Krishn, Shiv Ram; Jahan, Rahat; Banerjee, Kasturi; Batra, Surinder K; Jain, Maneesh

2015-03-01

Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to the pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emerging Potential of Natural Products for Targeting Mucins for Therapy Against Inflammation and Cancer

PubMed Central

Macha, Muzafar A.; Krishn, Shiv Ram; Jahan, Rahat; Banerjee, Kasturi; Batra, Surinder K.; Jain, Maneesh

2015-01-01

Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders and has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy. PMID:25624117

Evaluation of Antioxidant and Antiangiogenic Properties of Caesalpinia Echinata Extracts

PubMed Central

da Silva Gomes, Elisangela Christhianne Barbosa; Jimenez, George Chaves; da Silva, Luis Claudio Nascimento; de Sá, Fabrício Bezerra; de Souza, Karen Pena Cavalcanti; Paiva, Gerson S.; de Souza, Ivone Antônia

2014-01-01

Natural products contain important combinations of ingredients, which may to some extent help to modulate the effects produced by oxidation substrates in biological systems. It is known that substances capable of modulating the action of these oxidants on tissue may be important allies in the control of neovascularization in pathological processes. The aim of this study was to evaluate the antioxidant and antiangiogenic properties of an ethanol extract of Caesalpinia echinata. The evaluation of antioxidant properties was tested using two methods (DPPH inhibition and sequestration of nitric oxide). The antiangiogenic properties were evaluated using the inflammatory angiogenesis model in the corneas of rats. The extract of C. echinata demonstrated a high capacity to inhibit free radicals, with IC50 equal to 42.404 µg/mL for the DPPH test and 234.2 µg/mL for nitric oxide. Moreover, it showed itself capable of inhibiting the inflammatory angiogenic response by 77.49%. These data suggest that biochemical components belonging to the extract of C. echinata interfere in mechanisms that control the angiogenic process, mediated by substrates belonging to the arachidonic acid cascade, although the data described above also suggest that the NO buffer may contribute to some extent to the reduction in the angiogenic response. PMID:24563668