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Sample records for b-mediated inflammatory responses

  1. Ankrd2 is a modulator of NF-κB-mediated inflammatory responses during muscle differentiation

    PubMed Central

    Bean, C; Verma, N K; Yamamoto, D L; Chemello, F; Cenni, V; Filomena, M C; Chen, J; Bang, M L; Lanfranchi, G

    2014-01-01

    Adaptive responses of skeletal muscle regulate the nuclear shuttling of the sarcomeric protein Ankrd2 that can transduce different stimuli into specific adaptations by interacting with both structural and regulatory proteins. In a genome-wide expression study on Ankrd2-knockout or -overexpressing primary proliferating or differentiating myoblasts, we found an inverse correlation between Ankrd2 levels and the expression of proinflammatory genes and identified Ankrd2 as a potent repressor of inflammatory responses through direct interaction with the NF-κB repressor subunit p50. In particular, we identified Gsk3β as a novel direct target of the p50/Ankrd2 repressosome dimer and found that the recruitment of p50 by Ankrd2 is dependent on Akt2-mediated phosphorylation of Ankrd2 upon oxidative stress during myogenic differentiation. Surprisingly, the absence of Ankrd2 in slow muscle negatively affected the expression of cytokines and key calcineurin-dependent genes associated with the slow-twitch muscle program. Thus, our findings support a model in which alterations in Ankrd2 protein and phosphorylation levels modulate the balance between physiological and pathological inflammatory responses in muscle. PMID:24434510

  2. Overexpression of Sirtuin 6 suppresses cellular senescence and NF-κB mediated inflammatory responses in osteoarthritis development

    PubMed Central

    Wu, Yaosen; Chen, Linwei; Wang, Ye; Li, Wanli; Lin, Yan; Yu, Dongsheng; Zhang, Liang; Li, Fangcai; Pan, Zhijun

    2015-01-01

    The aim of our study was to evaluate if Sirt6, a NAD + dependent histone deacetylase, plays a protective role in cartilage degeneration by suppressing cellular senescence and inflammatory responses. The expression level of sirt6 in normal and OA human knee articular cartilage was compared by immunofluorescence and western blotting. The effect of sirt6 overexpression on replicative senescence of chondrocytes and NF-κB target genes expression was evaluated. Histological assessment of OA mice knee joint was carried out to assess the in vivo effects of sirt6 overexpression on mice chondrocytes. We found sirt6 level was significantly decreased in the articular chondrocytes of OA patients compare to normal human. SA-β-gal staining revealed that overexpression of sirt6 suppressed replicative senescence of chondrocytes. Meanwhile, the expression of NF-κB dependent genes were significantly attenuated by sirt6 overxpression. Safranin-O staining and OARSI score of knee joint cartilage in OA mice revealed that Lenti-Sirt6 intraarticular injection could protect mice chondrocytes from degeneration. These data strongly suggest that overexpression of Sirt6 can prevent OA development by reducing both the inflammatory response and chondrocytes senescence. Therefore, the development of specific activators of Sirt6 may have therapeutic potential for the treatment of OA. PMID:26639398

  3. hCLOCK Causes Rho-Kinase-Mediated Endothelial Dysfunction and NF-κB-Mediated Inflammatory Responses

    PubMed Central

    Tang, Xiao; Guo, Daqiao; Lin, Changpo; Shi, Zhenyu; Qian, Ruizhe; Fu, Weiguo; Liu, Jianjun; Li, Xu; Fan, Longhua

    2015-01-01

    Background. The human Circadian Locomotor Output Cycle protein Kaput (CLOCK) gene was originally discovered as a regulator of essential human daily rhythms. This seemingly innocuous gene was then found to be associated with a multitude of human malignancies, via several biochemical pathways. We aimed to further investigate the role of hCLOCK in the hypoxia-oxidative stress response system at the biochemical level. Methods. Expression levels of Rho GTPases were measured in normoxic and hypoxic states. The effect of hCLOCK on the hypoxic response was evaluated with the use of a retroviral shRNA vector system, a Rho inhibitor, and a ROS scavenger by analyzing expression levels of hCLOCK, Rho GTPases, and NF-κB pathway effectors. Finally, in vitro ROS production and tube formation in HUVECs were assessed. Results. Hypoxia induces ROS production via hCLOCK. hCLOCK activates the RhoA and NF-κB signaling pathways. Conversely, inhibition of hCLOCK deactivates these pathways. Furthermore, inhibition of RhoA or decreased levels of ROS attenuate these pathways, but inhibition of RhoA does not lead to decreased levels of ROS. Overall findings show that hypoxia increases the expression of hCLOCK, which leads to ROS production, which then activates the RhoA and NF-κB pathways. Conclusion. Our findings suggest that hypoxic states induce vascular oxidative damage and inflammation via hCLOCK-mediated production of ROS, with subsequent activation of the RhoA and NF-κB pathways. PMID:26583060

  4. Calcineurin inhibitors recruit protein kinases JAK2 and JNK, TLR signaling and the UPR to activate NF-κB-mediated inflammatory responses in kidney tubular cells

    SciTech Connect

    González-Guerrero, Cristian; Ocaña-Salceda, Carlos; Berzal, Sergio; Carrasco, Susana; Fernández-Fernández, Beatriz; and others

    2013-11-01

    The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are key drugs in current immunosuppressive regimes for solid organ transplantation. However, they are nephrotoxic and promote death and profibrotic responses in tubular cells. Moreover, renal inflammation is observed in CNI nephrotoxicity but the mechanisms are poorly understood. We have now studied molecular pathways leading to inflammation elicited by the CNIs in cultured and kidney tubular cells. Both CsA and tacrolimus elicited a proinflammatory response in tubular cells as evidenced by a transcriptomics approach. Transcriptomics also suggested several potential pathways leading to expression of proinflammatory genes. Validation and functional studies disclosed that in tubular cells, CNIs activated protein kinases such as the JAK2/STAT3 and TAK1/JNK/AP-1 pathways, TLR4/Myd88/IRAK signaling and the Unfolded Protein Response (UPR) to promote NF-κB activation and proinflammatory gene expression. CNIs also activated an Nrf2/HO-1-dependent compensatory response and the Nrf2 activator sulforaphane inhibited JAK2 and JNK activation and inflammation. A murine model of CsA nephrotoxicity corroborated activation of the proinflammatory pathways identified in cell cultures. Human CNIs nephrotoxicity was also associated with NF-κB, STAT3 and IRE1α activation. In conclusion, CNIs recruit several intracellular pathways leading to previously non-described proinflammatory actions in renal tubular cells. Identification of these pathways provides novel clues for therapeutic intervention to limit CNIs nephrotoxicity. - Highlights: • Molecular mechanisms modulating CNI renal inflammation were investigated. • Kinases, immune receptors and ER stress mediate the inflammatory response to CNIs. • Several intracellular pathways activate NF-κB in CNIs-treated tubular cells. • A NF-κB-dependent cytokine profile characterizes CNIs-induced inflammation. • CNI nephrotoxicity was associated to inflammatory

  5. Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-κB-mediated inflammatory response

    PubMed Central

    Xia, YF; Zhang, JH; Xu, ZF; Deng, XM

    2015-01-01

    Background: During mechanical ventilation, high end-inspiratory lung volume results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). The pathophysiology of ventilator-induced lung injury involves multiple mechanisms, such as excessive inflammation. And pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have anti-inflammatory activity. Objective: We investigated the effects of pyncogenol on ventilator-induced lung injury in rats. Methods: Rats were orally administrated with pycnogenol once (30 mg/kg) 2 days before lung injury induction with mechanical ventilation, then the rats were divided into three groups: lung-protective ventilation (LV group, n = 20), injurious ventilation (HV group, n = 20), HV + pycnogenol group (HV + Pyc group, n = 20). Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses. Results: Pretreatment with pycnogenol could markedly decrease lung wet/dry ratio, lower myeloperoxidase (MPO) activity and total protein concentration and reduce the production of TNF-α, IL-6, IL-1β and MIP-2 in the BALF in ventilator-induced lung injury rats. Additionally, pycnogenol improved the histology of the lung and significantly inhibited the phosphorylation of NF-κB p65 and the degradation of IκB-α. Conclusion: Pycnogenol treatment could attenuate ventilator-induced lung injury in rats, at least in part, through its ability to reduce the production of inflammatory cytokines via inhibiting the activation of NF-κB, indicating it as a potential therapeutic candidate for ventilator-induced lung injury. PMID:25932110

  6. 4-Isopropyl-2,6-bis(1-phenylethyl)aniline 1, an Analogue of KTH-13 Isolated from Cordyceps bassiana, Inhibits the NF-κB-Mediated Inflammatory Response.

    PubMed

    Yang, Woo Seok; Ratan, Zubair Ahmed; Kim, Gihyeon; Lee, Yunmi; Kim, Mi-Yeon; Kim, Jong-Hoon; Cho, Jae Youl

    2015-01-01

    The Cordyceps species has been a good source of compounds with anticancer and anti-inflammatory activities. Recently, we reported a novel compound (4-isopropyl-2,6-bis(1-phenylethyl)phenol, KTH-13) with anticancer activity isolated from Cordyceps bassiana and created several derivatives to increase its pharmacological activity. In this study, we tested one of the KTH-013 derivatives, 4-isopropyl-2,6-bis(1-phenylethyl)aniline 1 (KTH-13-AD1), with regard to anti-inflammatory activity under macrophage-mediated inflammatory conditions. KTH-13-AD1 clearly suppressed the production of nitric oxide (NO) and reactive oxygen species (ROS) in lipopolysaccharide (LPS) and sodium nitroprusside- (SNP-) treated macrophage-like cells (RAW264.7 cells). Similarly, this compound also reduced mRNA expression of inducible NO synthase (iNOS) and tumor necrosis factor-α (TNF-α), as analyzed by RT-PCR and real-time PCR. Interestingly, KTH-13-AD1 strongly diminished NF-κB-mediated luciferase activities and nuclear translocation of NF-κB family proteins. In accordance, KTH-13-AD1 suppressed the upstream signaling pathway of NF-κB activation, including IκBα, IKKα/β, AKT, p85/PI3K, and Src in a time- and dose-dependent manner. The autophosphorylation of Src and NF-κB observed during the overexpression of Src was also suppressed by KTH-13-AD1. These results strongly suggest that KTH-13-AD1 has strong anti-inflammatory features mediated by suppression of the Src/NF-κB regulatory loop. PMID:26819495

  7. 4-Isopropyl-2,6-bis(1-phenylethyl)aniline 1, an Analogue of KTH-13 Isolated from Cordyceps bassiana, Inhibits the NF-κB-Mediated Inflammatory Response

    PubMed Central

    Yang, Woo Seok; Ratan, Zubair Ahmed; Kim, Gihyeon; Lee, Yunmi; Kim, Mi-Yeon; Kim, Jong-Hoon; Cho, Jae Youl

    2015-01-01

    The Cordyceps species has been a good source of compounds with anticancer and anti-inflammatory activities. Recently, we reported a novel compound (4-isopropyl-2,6-bis(1-phenylethyl)phenol, KTH-13) with anticancer activity isolated from Cordyceps bassiana and created several derivatives to increase its pharmacological activity. In this study, we tested one of the KTH-013 derivatives, 4-isopropyl-2,6-bis(1-phenylethyl)aniline 1 (KTH-13-AD1), with regard to anti-inflammatory activity under macrophage-mediated inflammatory conditions. KTH-13-AD1 clearly suppressed the production of nitric oxide (NO) and reactive oxygen species (ROS) in lipopolysaccharide (LPS) and sodium nitroprusside- (SNP-) treated macrophage-like cells (RAW264.7 cells). Similarly, this compound also reduced mRNA expression of inducible NO synthase (iNOS) and tumor necrosis factor-α (TNF-α), as analyzed by RT-PCR and real-time PCR. Interestingly, KTH-13-AD1 strongly diminished NF-κB-mediated luciferase activities and nuclear translocation of NF-κB family proteins. In accordance, KTH-13-AD1 suppressed the upstream signaling pathway of NF-κB activation, including IκBα, IKKα/β, AKT, p85/PI3K, and Src in a time- and dose-dependent manner. The autophosphorylation of Src and NF-κB observed during the overexpression of Src was also suppressed by KTH-13-AD1. These results strongly suggest that KTH-13-AD1 has strong anti-inflammatory features mediated by suppression of the Src/NF-κB regulatory loop. PMID:26819495

  8. Oxytocin activates NF-κB-mediated inflammatory pathways in human gestational tissues.

    PubMed

    Kim, Sung Hye; MacIntyre, David A; Firmino Da Silva, Maria; Blanks, Andrew M; Lee, Yun S; Thornton, Steven; Bennett, Phillip R; Terzidou, Vasso

    2015-03-01

    Human labour, both at term and preterm, is preceded by NF-κB-mediated inflammatory activation within the uterus, leading to myometrial activation, fetal membrane remodelling and cervical ripening. The stimuli triggering inflammatory activation in normal human parturition are not fully understood. We show that the neurohypophyseal peptide, oxytocin (OT), activates NF-κB and stimulates downstream inflammatory pathways in human gestational tissues. OT stimulation (1 pM-100 nM) specifically via its receptor (OTR) in human myometrial and amnion primary cells led to MAPK and NF-κB activation within 15 min and maximal p65-subunit nuclear translocation within 30 min. Both in human myometrium and amnion, OT-induced activation of the canonical NF-κB pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKKβ inhibition (TPCA1; 10 µM) suppressed OT-induced NF-κB-p65 phosphorylation, whereas p65-siRNA knockdown reduced basal and OT-induced COX-2 levels in myometrium and amnion. In both gestational tissues, MEK1/2 (U0126; 10 µM) or p38 inhibition (SB203580; 10 µM) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-κB in amnion is MAPK-dependent. Our data provide new insight into the OT/OTR system in human parturition and suggest that its therapeutic modulation could be a strategy for regulating both contractile and inflammatory pathways in the clinical context of term/preterm labour. PMID:25451977

  9. GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis.

    PubMed

    Hussman, J P; Beecham, A H; Schmidt, M; Martin, E R; McCauley, J L; Vance, J M; Haines, J L; Pericak-Vance, M A

    2016-07-01

    To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on the significance of linkage disequilibrium blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery. The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility. PMID:27278126

  10. GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

    PubMed Central

    Hussman, J P; Beecham, A H; Schmidt, M; Martin, E R; McCauley, J L; Vance, J M; Haines, J L; Pericak-Vance, M A

    2016-01-01

    To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on the significance of linkage disequilibrium blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery. The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility. PMID:27278126

  11. Hormonal control of inflammatory responses

    PubMed Central

    Farsky, Sandra P.

    1993-01-01

    Almost any stage of inflammatory and immunological responses is affected by hormone actions. This provides the basis for the suggestion that hormones act as modulators of the host reaction against trauma and infection. Specific hormone receptors are detected in the reactive structures in inflamed areas and binding of hormone molecules to such receptors results in the generation of signals that influence cell functions relevant for the development of inflammatory responses. Diversity of hormonal functions accounts for recognized pro- and anti-inflammatory effects exerted by these substances. Most hormone systems are capable of influencing inflammatory events. Insulin and glucocorticoids, however, exert direct regulatory effects at concentrations usually found in plasma. Insulin is endowed with facilitatory actions on vascular reactivity to inflammatory mediators and inflammatory cell functions. Increased concentrations of circulating glucocorticoids at the early stages of inflammation results in downregulation of inflammatory responses. Oestrogens markedly reduce the response to injury in a variety of experimental models. Glucagon and thyroid hormones exert indirect anti-inflammatory effects mediated by the activity of the adrenal cortex. Accordingly, inflammation is not only merely a local response, but a hormone-controlled process. PMID:18475521

  12. PDLIM1 inhibits NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm

    PubMed Central

    Ono, Rumiko; Kaisho, Tsuneyasu; Tanaka, Takashi

    2015-01-01

    Understanding the regulatory mechanisms for the NF-κB transcription factor is key to control inflammation. IκBα maintains NF-κB in an inactive form in the cytoplasm of unstimulated cells, whereas nuclear NF-κB in activated cells is degraded by PDLIM2, a nuclear ubiquitin E3 ligase that belongs to a LIM protein family. How NF-κB activation is negatively controlled, however, is not completely understood. Here we show that PDLIM1, another member of LIM proteins, negatively regulates NF-κB-mediated signaling in the cytoplasm. PDLIM1 sequestered p65 subunit of NF-κB in the cytoplasm and suppressed its nuclear translocation in an IκBα-independent, but α-actinin-4-dependent manner. Consistently, PDLIM1 deficiency lead to increased levels of nuclear p65 protein, and thus enhanced proinflammatory cytokine production in response to innate stimuli. These studies reveal an essential role of PDLIM1 in suppressing NF-κB activation and suggest that LIM proteins comprise a new family of negative regulators of NF-κB signaling through different mechanisms. PMID:26679095

  13. Molecular cues guiding inflammatory responses.

    PubMed

    Barreiro, Olga; Martín, Pilar; González-Amaro, Roberto; Sánchez-Madrid, Francisco

    2010-05-01

    Alarm signals generated at inflammatory foci reach the vascular lumen to attract immune cells towards the affected tissue. Different leucocyte subsets decipher and integrate these complex signals in order to make adequate decisions for their migration towards the inflamed tissue. Soluble cues (cytokines and chemokines) and membrane receptors in both endothelium and leucocytes orchestrate the coordinated recruitment of specific inflammatory cell subsets. All these molecules are spatio-temporally organized in specialized structures at the luminal side of endothelium and the leucocyte membrane or are generated as chemical gradients in the damaged tissue. Thus, the repertoire of chemokines and their receptors as well as adhesion molecules expressed by each leucocyte subset determine their recruitment for participation in specific inflammatory pathologies. Whenever inflammatory signals are altered or misprocessed, inflammation can become chronic, causing extensive tissue damage. To combat chronic inflammation and autoimmune diseases, novel therapeutic strategies attempt to silence the predominant signals in each inflammatory scenario. In this review, we provide a general overview of all these aspects related to the molecular regulation of leucocyte guidance in inflammatory responses. PMID:20053659

  14. Inflammatory response and extracorporeal circulation.

    PubMed

    Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

    2015-06-01

    Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. PMID:26060024

  15. 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

  16. Phytochrome B-mediated activation of lipoxygenase modulates an excess red light-induced defence response in Arabidopsis

    PubMed Central

    Zhao, Yuanyuan; Zhou, Jun; Xing, Da

    2014-01-01

    Lipoxygenase (LOX), a non-haem-iron-containing dioxygenase, is activated under various biotic or abiotic stresses to trigger a series resistance response, but the molecular mechanism of LOX activation remains unclear. This work investigated the activation of LOX during the plant defence response induced by excess red light (RL). In conditions of RL-induced defence, Arabidopsis LOX activity and transcription levels of LOX2, LOX3, and LOX4 were both upregulated. Under RL, phytochrome B promoted the degradation of phytochrome-interacting factor 3 (PIF3), a factor that inhibited the expression levels of LOXs, and thus the transcription levels of LOX2, LOX3, and LOX4 were increased. Upon pathogen infection, the activity of mitogen-activated protein kinase 3 (MPK3) and MPK6 was increased in plants pre-treated with RL. Moreover, experiments with the inhibitor PD98059 and mutants mpk3 and mpk6-2 demonstrated that MPK3 and MPK6 were both responsible for LOX activation. Further results showed that, in response to RL, an increase in cytoplasmic calcium concentration and upregulation of calmodulin 3 (CaM3) transcript level occurred upstream of MPK3 and MPK6 activation. Collectively, these results suggested that activation of LOX both at the transcript level and in terms of activity modulates the defence response induced by RL, providing a new insight into the mechanistic study of LOX during plant defences. PMID:24916071

  17. Tomato Protein Kinase 1b Mediates Signaling of Plant Responses to Necrotrophic Fungi and Insect Herbivory[W

    PubMed Central

    AbuQamar, Synan; Chai, Mao-Feng; Luo, Hongli; Song, Fengming; Mengiste, Tesfaye

    2008-01-01

    The tomato protein kinase 1 (TPK1b) gene encodes a receptor-like cytoplasmic kinase localized to the plasma membrane. Pathogen infection, mechanical wounding, and oxidative stress induce expression of TPK1b, and reducing TPK1b gene expression through RNA interference (RNAi) increases tomato susceptibility to the necrotrophic fungus Botrytis cinerea and to feeding by larvae of tobacco hornworm (Manduca sexta) but not to the bacterial pathogen Pseudomonas syringae. TPK1b RNAi seedlings are also impaired in ethylene (ET) responses. Notably, susceptibility to Botrytis and insect feeding is correlated with reduced expression of the proteinase inhibitor II gene in response to Botrytis and 1-aminocyclopropane-1-carboxylic acid, the natural precursor of ET, but wild-type expression in response to mechanical wounding and methyl-jasmonate. TPK1b functions independent of JA biosynthesis and response genes required for resistance to Botrytis. TPK1b is a functional kinase with autophosphorylation and Myelin Basis Protein phosphorylation activities. Three residues in the activation segment play a critical role in the kinase activity and in vivo signaling function of TPK1b. In sum, our findings establish a signaling role for TPK1b in an ET-mediated shared defense mechanism for resistance to necrotrophic fungi and herbivorous insects. PMID:18599583

  18. DWD HYPERSENSITIVE TO UV-B 1 is negatively involved in UV-B mediated cellular responses in Arabidopsis.

    PubMed

    Kim, Sang-Hoon; Kim, Hani; Seo, Kyoung-In; Kim, Soon-Hee; Chung, Sunglan; Huang, Xi; Yang, Panyu; Deng, Xing Wang; Lee, Jae-Hoon

    2014-12-01

    Among T-DNA insertion mutants of various cullin4-RING ubiquitin E3 ligase (CRL4) substrate receptors, one mutant that exhibits enhanced sensitivity in response to ultraviolet-B (UV-B) illumination has been isolated and its corresponding gene has been named DWD HYPERSENSITIVE TO UV-B 1 (DHU1) in Arabidopsis. dhu1 lines showed much shorter hypocotyls than those in wild type under low doses of UV-B. Other light did not alter hypocotyl growth patterns in dhu1, indicating the hypersensitivity of dhu1 is restricted to UV-B. DHU1 was upregulated by more than two times in response to UV-B application of 1.5 μmol m(-2) s(-1), implying its possible involvement in UV-B signaling. DHU1 is able to bind to DDB1, an adaptor of CRL4; accordingly, DHU1 is thought to act as a substrate receptor of CRL4. Microarray data generated from wild-type and dhu1 under low doses of UV-B revealed that 209 or 124 genes were upregulated or downregulated by more than two times in dhu1 relative to wild type, respectively. About 23.4 % of the total upregulated genes in dhu1 were upregulated by more than five times in response to UV-B based on the AtGenExpress Visualization Tool data, while only about 1.4 % were downregulated to the same degree by UV-B, indicating that loss of DHU1 led to the overall enhancement of the upregulation of UV-B inducible genes. dhu1 also showed altered responsiveness under high doses of UV-B. Taken together, these findings indicate that DHU1 is a potent CRL4 substrate receptor that may function as a negative regulator of UV-B response in Arabidopsis. PMID:25193399

  19. Exposure of Bacillus subtilis to Low Pressure (5 Kilopascals) Induces Several Global Regulons, Including Those Involved in the SigB-Mediated General Stress Response

    PubMed Central

    Waters, Samantha M.; Robles-Martínez, José A.

    2014-01-01

    Studies of how microorganisms respond to pressure have been limited mostly to the extreme high pressures of the deep sea (i.e., the piezosphere). In contrast, despite the fact that the growth of most bacteria is inhibited at pressures below ∼2.5 kPa, little is known of microbial responses to low pressure (LP). To study the global LP response, we performed transcription microarrays on Bacillus subtilis cells grown under normal atmospheric pressure (∼101 kPa) and a nearly inhibitory LP (5 kPa), equivalent to the pressure found at an altitude of ∼20 km. Microarray analysis revealed altered levels of 363 transcripts belonging to several global regulons (AbrB, CcpA, CodY, Fur, IolR, ResD, Rok, SigH, Spo0A). Notably, the highest number of upregulated genes, 86, belonged to the SigB-mediated general stress response (GSR) regulon. Upregulation of the GSR by LP was confirmed by monitoring the expression of the SigB-dependent ctc-lacZ reporter fusion. Measuring transcriptome changes resulting from exposure of bacterial cells to LP reveals insights into cellular processes that may respond to LP exposure. PMID:24878601

  20. Mucosal Inflammatory Response to Salmonella typhimurium Infection

    PubMed Central

    Patel, Samir; McCormick, Beth A.

    2014-01-01

    The human intestinal epithelium consists of a single layer of epithelial cells that forms a barrier against food antigens and the resident microbiota within the lumen. This delicately balanced organ functions in a highly sophisticated manner to uphold the fidelity of the intestinal epithelium and to eliminate pathogenic microorganisms. On the luminal side, this barrier is fortified by a thick mucus layer, and on the serosal side exists the lamina propria containing a resident population of immune cells. Pathogens that are able to breach this barrier disrupt the healthy epithelial lining by interfering with the regulatory mechanisms that govern the normal balance of intestinal architecture and function. This disruption results in a coordinated innate immune response deployed to eliminate the intruder that includes the release of antimicrobial peptides, activation of pattern-recognition receptors, and recruitment of a variety of immune cells. In the case of Salmonella enterica serovar typhimurium (S. typhimurium) infection, induction of an inflammatory response has been linked to its virulence mechanism, the type III secretion system (T3SS). The T3SS secretes protein effectors that exploit the host’s cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response. As the role of the intestinal epithelium in initiating an immune response has been increasingly realized, this review will highlight recent research that details progress made in understanding mechanisms underlying the mucosal inflammatory response to Salmonella infection, and how such inflammatory responses impact pathogenic fitness of this organism. PMID:25071772

  1. Natural Products: Insights into Leishmaniasis Inflammatory Response

    PubMed Central

    Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

    2015-01-01

    Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

  2. NEFAs activate the oxidative stress-mediated NF-κB signaling pathway to induce inflammatory response in calf hepatocytes.

    PubMed

    Shi, Xiaoxia; Li, Dangdang; Deng, Qinghua; Li, Yu; Sun, Guoquan; Yuan, Xue; Song, Yuxiang; Wang, Zhe; Li, Xiaobing; Li, Xinwei; Liu, Guowen

    2015-01-01

    Non-esterified fatty acids (NEFAs) are important induction factors of inflammatory responses in some metabolic diseases. High plasma levels of NEFAs and oxidative stress exist in the dairy cows with ketosis. The aim of this study was to investigate whether high levels of NEFAs can induce inflammatory response and the specific molecular mechanism in the hepatocytes of dairy cow. In vitro, primary cultured bovine hepatocytes were treated with different concentrations of NEFAs, PDTC (an NF-κB inhibitor) and NAC (an antioxidant). NEFAs significantly activated NF-κB pathway. Activated NF-κB upregulated the release of pro-inflammatory cytokines, thereby inducing inflammatory response in bovine hepatocytes. When PDTC was added, activation of NF-κB-mediated inflammatory response induced by NEFAs was inhibited. NEFAs treatment results in the overproduction of the markers of oxidative stress, reactive oxygen species (ROS) and malondialdehyde (MDA), which were ameliorated by NAC treatment. These increased ROS and MDA were caused by decreasing activity of antioxidant system, including glutathione peroxidase, superoxide dismutase and catalase, in bovine hepatocytes treated with NEFAs. NAC also ameliorated NEFAs-mediated NF-κB activation and the release of pro-inflammatory cytokines. These results indicate that high concentrations of NEFAs can induce cattle hepatocytes inflammatory response through activating the oxidative stress-mediated NF-κB signaling pathway. PMID:25465477

  3. Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-κB mediated and supports innate and adaptive anti-tumour immune priming

    PubMed Central

    2011-01-01

    Background As well as inducing direct oncolysis, reovirus treatment of melanoma is associated with activation of innate and adaptive anti-tumour immune responses. Results Here we characterise the effects of conditioned media from reovirus-infected, dying human melanoma cells (reoTCM), in the absence of live virus, to address the immune bystander potential of reovirus therapy. In addition to RANTES, IL-8, MIP-1α and MIP-1β, reovirus-infected melanoma cells secreted eotaxin, IP-10 and the type 1 interferon IFN-β. To address the mechanisms responsible for the inflammatory composition of reoTCM, we show that IL-8 and IFN-β secretion by reovirus-infected melanoma cells was associated with activation of NF-κB and decreased by pre-treatment with small molecule inhibitors of NF-κB and PKR; specific siRNA-mediated knockdown further confirmed a role for PKR. This pro-inflammatory milieu induced a chemotactic response in isolated natural killer (NK) cells, dendritic cells (DC) and anti-melanoma cytotoxic T cells (CTL). Following culture in reoTCM, NK cells upregulated CD69 expression and acquired greater lytic potential against tumour targets. Furthermore, melanoma cell-loaded DC cultured in reoTCM were more effective at priming adaptive anti-tumour immunity. Conclusions These data demonstrate that the PKR- and NF-κB-dependent induction of pro-inflammatory molecules that accompanies reovirus-mediated killing can recruit and activate innate and adaptive effector cells, thus potentially altering the tumour microenvironment to support bystander immune-mediated therapy as well as direct viral oncolysis. PMID:21338484

  4. Analyzing inflammatory response as excitable media

    NASA Astrophysics Data System (ADS)

    Yde, Pernille; Høgh Jensen, Mogens; Trusina, Ala

    2011-11-01

    The regulatory system of the transcription factor NF-κB plays a great role in many cell functions, including inflammatory response. Interestingly, the NF-κB system is known to up-regulate production of its own triggering signal—namely, inflammatory cytokines such as TNF, IL-1, and IL-6. In this paper we investigate a previously presented model of the NF-κB, which includes both spatial effects and the positive feedback from cytokines. The model exhibits the properties of an excitable medium and has the ability to propagate waves of high cytokine concentration. These waves represent an optimal way of sending an inflammatory signal through the tissue as they create a chemotactic signal able to recruit neutrophils to the site of infection. The simple model displays three qualitatively different states; low stimuli leads to no or very little response. Intermediate stimuli leads to reoccurring waves of high cytokine concentration. Finally, high stimuli leads to a sustained high cytokine concentration, a scenario which is toxic for the tissue cells and corresponds to chronic inflammation. Due to the few variables of the simple model, we are able to perform a phase-space analysis leading to a detailed understanding of the functional form of the model and its limitations. The spatial effects of the model contribute to the robustness of the cytokine wave formation and propagation.

  5. Collective cell migration during inflammatory response

    NASA Astrophysics Data System (ADS)

    Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

  6. Inflammatory responses to infection: the Dutch contribution.

    PubMed

    Nolte, Martijn A; van der Meer, Jos W M

    2014-12-01

    At any given moment, our body is under attack by a large variety of pathogens, which aim to enter and use our body to propagate and disseminate. The extensive cellular and molecular complexity of our immune system enables us to efficiently eliminate invading pathogens or at least develop a condition in which propagation of the microorganism is reduced to a minimum. Yet, the evolutionary pressure on pathogens to circumvent our immune defense mechanisms is immense, which continuously leads to the development of novel pathogenic strains that challenge the health of mankind. Understanding this battle between pathogen and the immune system has been a fruitful area of immunological research over the last century and will continue to do so for many years. In this review, which has been written on the occasion of the 50th anniversary of the Dutch Society for Immunology, we provide an overview of the major contributions that Dutch immunologists and infection biologists have made in the last decades on the inflammatory response to viral, bacterial, fungal or parasitic infections. We focus on those studies that have addressed both the host and the pathogen, as these are most interesting from an immunological point of view. Although it is not possible to completely cover this comprehensive research field, this review does provide an interesting overview of Dutch research on inflammatory responses to infection. PMID:25455597

  7. Scorpion venom and the inflammatory response.

    PubMed

    Petricevich, Vera L

    2010-01-01

    Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability. PMID:20300540

  8. Scorpion Venom and the Inflammatory Response

    PubMed Central

    Petricevich, Vera L.

    2010-01-01

    Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability. PMID:20300540

  9. Noncanonical WNT-5B signaling induces inflammatory responses in human lung fibroblasts.

    PubMed

    van Dijk, Eline M; Menzen, Mark H; Spanjer, Anita I R; Middag, Laurens D C; Brandsma, Corry-Anke A; Gosens, Reinoud

    2016-06-01

    COPD is a progressive chronic lung disease characterized by pulmonary inflammation. Several recent studies indicate aberrant expression of WNT ligands and Frizzled receptors in the disease. For example, WNT-5A/B ligand expression was recently found to be increased in lung fibroblasts of COPD patients. However, possible effects of WNT-5A and WNT-5B on inflammation have not been investigated yet. In this study, we assessed the regulation of inflammatory cytokine release in response to WNT-5A/B signaling in human lung fibroblasts. Primary human fetal lung fibroblasts (MRC-5), and primary lung fibroblasts from COPD patients and non-COPD controls were treated with recombinant WNT-5A or WNT-5B to assess IL-6 and CXCL8 cytokine secretion and gene expression levels. Following WNT-5B, and to a lesser extent WNT-5A stimulation, fibroblasts showed increased IL-6 and CXCL8 cytokine secretion and mRNA expression. WNT-5B-mediated IL-6 and CXCL8 release was higher in fibroblasts from COPD patients than in non-COPD controls. In MRC-5 fibroblasts, WNT-5B-induced CXCL8 release was mediated primarily via the Frizzled-2 receptor and TAK1 signaling, whereas canonical β-catenin signaling was not involved. In further support of noncanonical signaling, we showed activation of JNK, p38, and p65 NF-κB by WNT-5B. Furthermore, inhibition of JNK and p38 prevented WNT-5B-induced IL-6 and CXCL8 secretion, whereas IKK inhibition prevented CXCL8 secretion only, indicating distinct pathways for WNT-5B-induced IL-6 and CXCL8 release. WNT-5B induces IL-6 and CXCL8 secretion in pulmonary fibroblasts. In summary, WNT-5B mediates this via Frizzled-2 and TAK1. As WNT-5 signaling is increased in COPD, this WNT-5-induced inflammatory response could represent a therapeutic target. PMID:27036869

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

    PubMed Central

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

    2016-01-01

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

  11. Transport induced inflammatory responses in horses.

    PubMed

    Wessely-Szponder, J; Bełkot, Z; Bobowiec, R; Kosior-Korzecka, U; Wójcik, M

    2015-01-01

    Deleterious response to road transport is an important problem in equine practice. It determines different physiological, immunological and metabolic changes which lead to increased susceptibility to several disorders such as pneumonia, diarrhea, colics, laminitis, injuries and rhabdomyolisis. The aim of our study was to look for possible relationships between transportation of female young and older horses over a long and short distance and an inflammatory state reflected by an increase of acute phase protein concentration, oxidative stress and muscle injury. The study was conducted on 24 cold-blooded female horses divided into four groups. Six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 550 km, six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 50 km. Plasma and serum were obtained from blood samples taken before transportation (T0), immediately after transportation (T1) and at an abattoir during slaughter (T2). In these samples fibrinogen, MDA, AST and CK were assessed. Fibrinogen increased in all studied groups especially in fillies after long distance transportation, where it reached 205±7.07 mg/dl before transportation, 625±35.35 mg/dl after transportation, and 790±14.14 mg/dl during slaughter. MDA concentrations rose after transportation and reached the maximal level during slaughter. CK activity was more elevated after short transportation in younger horses, whereas initial activity of AST was higher in older horses. We estimated that intensified responses from acute phase, oxidative stress and muscle injury parameters indicated an inflammatory state. PMID:26172192

  12. Alert cell strategy: mechanisms of inflammatory response and organ protection.

    PubMed

    Hatakeyama, Noboru; Matsuda, Naoyuki

    2014-01-01

    Systemic inflammatory response syndrome (SIRS) is triggered by various factors such as surgical operation, trauma, burn injury, ischemia, pancreatitis and bacterial translocation. Sepsis is a SIRS associated with bacterial infection. SIRS and sepsis tend to trigger excessive production of inflammatory cytokines and other inflammatory molecules and induce multiple organ failure, such as acute lung injury, acute kidney injury and inflammatory cardiac injury. Epithelial and endothelial cells in some major organs express inflammatory receptors on the plasma membrane and work as alert cells for inflammation, and regulation of these alert cells could have a relieving effect on the inflammatory response. In inflammatory conditions, initial cardiac dysfunction is mediated by decreased preload and adequate infusion therapy is required. Tachyarrhythmia is a complication of inflammatory conditions and early control of the inflammatory reaction would prevent the structural remodeling that is resistant to therapies. Furthermore, there seems to be crosstalk between major organs with a central focus on the kidneys in inflammatory conditions. As an alert cell strategy, volatile anesthetics, sevoflurane and isoflurane, seem to have anti-inflammatory effects, and both experimental and clinical studies have shown the beneficial effects of these drugs in various settings of inflammatory conditions. On the other hand, in terms of intravenous anesthetics, propofol and ketamine, their current status is still controversial as there is a lack of confirmatory evidence on whether they have an organ-protective effect in inflammatory conditions. The local anesthetic lidocaine suppressed inflammatory responses upon both systemic and local administration. For the control of inflammatory conditions, anesthetic agents may be a target of drug development in accordance with other treatments and drugs. PMID:25229471

  13. Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin.

    PubMed

    Moser, Jill; Heeringa, Peter; Jongman, Rianne M; Zwiers, Peter J; Niemarkt, Anita E; Yan, Rui; de Graaf, Inge A; Li, Ranran; Ravasz Regan, Erzsébet; Kümpers, Philipp; Aird, William C; van Nieuw Amerongen, Geerten P; Zijlstra, Jan G; Molema, Grietje; van Meurs, Matijs

    2016-06-01

    Sepsis is a systemic inflammatory response to infections associated with organ failure that is the most frequent cause of death in hospitalized patients. Exaggerated endothelial activation, altered blood flow, vascular leakage, and other disturbances synergistically contribute to sepsis-induced organ failure. The underlying signaling events associated with endothelial proinflammatory activation are not well understood, yet they likely consist of molecular pathways that act in an endothelium-specific manner. We found that LPS, a critical factor in the pathogenesis of sepsis, is internalized by endothelial cells, leading to intracellular signaling without the need for priming as found recently in immune cells. By identifying a novel role for retinoic acid-inducible gene-I (RIG-I) as a central regulator of endothelial activation functioning independent of TLR4, we provide evidence that the current paradigm of TLR4 solely being responsible for LPS-mediated endothelial responses is incomplete. RIG-I, as well as the adaptor protein mitochondrial antiviral signaling protein, regulates NF-κB-mediated induction of adhesion molecules and proinflammatory cytokine expression in response to LPS. Our findings provide essential new insights into the proinflammatory signaling pathways in endothelial cells and suggest that combined endothelial-specific inhibition of RIG-I and TLR4 will provide protection from aberrant endothelial responses associated with sepsis. PMID:27183587

  14. Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

    PubMed Central

    Yi, Young-Su; Son, Young-Jin; Ryou, Chongsuk; Sung, Gi-Ho; Kim, Jong-Hoon; Cho, Jae Youl

    2014-01-01

    Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases. PMID:25045209

  15. Candida albicans infection leads to barrier breakdown and a MAPK/NF-κB mediated stress response in the intestinal epithelial cell line C2BBe1.

    PubMed

    Böhringer, Michael; Pohlers, Susann; Schulze, Sylvie; Albrecht-Eckardt, Daniela; Piegsa, Judith; Weber, Michael; Martin, Ronny; Hünniger, Kerstin; Linde, Jörg; Guthke, Reinhard; Kurzai, Oliver

    2016-07-01

    Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa, has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time-resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-κB and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-κB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-κB was experimentally validated. Furthermore, inhibition of NF-κB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-κB activation as an important protective signalling pathway in the response of epithelial cells to C. albicans. PMID:26752615

  16. The Modulation of Hepatitis C Virus 1a Replication by PKR is Dependent on NF-kB Mediated Interferon Beta Response in Huh7.5.1 Cells

    PubMed Central

    Zhang, Lumin; Alter, Harvey J.; Wang, Haiping; Jia, Shuaizheng; Wang, Ena; Marincola, Francesco M.; Shih, Jams W-K.; Wang, Richard Y.

    2013-01-01

    Protein kinase R (PKR), a sensor of double-stranded RNA, plays an important role in the host response to viral infection. Hepatitis C genotype 2a virus (HCV 2a) has been shown to induce PKR activation to suppress the translation of antiviral interferon stimulated genes (ISGs), suggesting that PKR inhibitor can be beneficial for treating chronically HCV-infected patients in conjunction with interferon alpha and ribavirin. However, in this study, we found that PKR inhibition using siRNA PKR, shRNA PKR or PKR inhibitor enhanced HCV 1a replication and rendered Huh7.5.1 cells more susceptible to HCV1a infection. Additionally, PKR silencing suppressed NF-kB activation and NF-kB mediated STAT1 phosphorylation in Huh7.5.1 cells and HCV1a persistently-infected Huh7.5.1 cells (2HDD4). These effects were accompanied by a reduction of interferon beta response and thereby enhanced HCV1a replication in Huh7.5.1 cells. We conclude that host cells can employ PKR activation to restrict HCV1a replication through regulation of NF-kB expression. PMID:23399035

  17. Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures.

    PubMed

    Shin, H J; Kim, H; Heo, R W; Kim, H J; Choi, W S; Kwon, H M; Roh, G S

    2014-07-01

    Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/-) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/-) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/-) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target. PMID:24608792

  18. Hypoxia Promotes the Inflammatory Response and Stemness Features in Visceral Fat Stem Cells From Obese Subjects.

    PubMed

    Petrangeli, Elisa; Coroniti, Giuseppe; Brini, Anna T; de Girolamo, Laura; Stanco, Deborah; Niada, Stefania; Silecchia, Gianfranco; Morgante, Emanuela; Lubrano, Carla; Russo, Matteo A; Salvatori, Luisa

    2016-03-01

    Low-grade chronic inflammation is a salient feature of obesity and many associated disorders. This condition frequently occurs in central obesity and is connected to alterations of the visceral adipose tissue (AT) microenvironment. Understanding how obesity is related to inflammation may allow the development of therapeutics aimed at improving metabolic parameters in obese patients. To achieve this aim, we compared the features of two subpopulations of adipose-derived stem cells (ASC) isolated from both subcutaneous and visceral AT of obese patients with the features of two subpopulations of ASC from the same isolation sites of non-obese individuals. In particular, the behavior of ASC of obese versus non-obese subjects during hypoxia, which occurs in obese AT and is an inducer of the inflammatory response, was evaluated. Obesity deeply influenced ASC from visceral AT (obV-ASC); these cells appeared to exhibit clearly distinguishable morphology and ultrastructure as well as reduced proliferation, clonogenicity and expression of stemness, differentiation and inflammation-related genes. These cells also exhibited a deregulated response to hypoxia, which induced strong tissue-specific NF-kB activation and an NF-kB-mediated increase in inflammatory and fibrogenic responses. Moreover, obV-ASC, which showed a less stem-like phenotype, recovered stemness features after hypoxia. Our findings demonstrated the peculiar behavior of obV-ASC, their influence on the obese visceral AT microenvironment and the therapeutic potential of NF-kB inhibitors. These novel findings suggest that the deregulated hyper-responsiveness to hypoxic stimulus of ASC from visceral AT of obese subjects may contribute via paracrine mechanisms to low-grade chronic inflammation, which has been implicated in obesity-related morbidity. PMID:26224080

  19. Macrophage Expression of Inflammatory Genes in Response to EMCV Infection

    PubMed Central

    Shaheen, Zachary R.; Corbett, John A.

    2015-01-01

    The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression. PMID:26295266

  20. The systemic inflammatory response in heart failure.

    PubMed

    Anderson

    2000-09-01

    The physiologic diagnosis of heart failure has changed very little over the past several decades: heart failure is the inability of the cardiac output to meet the metabolic demands of the organism. The clinical definition of heart failure (also relatively unchanged) describes it as ventricular dysfunction that is accompanied by reduced exercise tolerance. Our understanding of the true pathophysiologic processes involved in heart failure have, however, changed. We have moved from thinking of heart failure as primarily a circulatory phenomenon to seeing it as a pathophysiologic state under the control of multiple complex systems. Over the past several years the dramatic explosion of research in the fields of immunology and immunopathology have added an additional piece to the puzzle that defines heart failure and have lead to an understanding of heart failure, at least in some part, as an 'inflammatory disease'. In this review we will examine several of the key inflammatory mediators as they relate to heart failure while at the same time attempting to define the source(s) of these mediators. We will examine key elements of the inflammatory cascade as they relate to heart failure such as: cytokines, 'proximal mediators' (e.g. NF-kappaB), and distal mediators (e.g. nitric oxide). We will end with a discussion of the potential therapeutic role of anti-inflammatory strategies in the future treatment of heart failure. Also, throughout the review we will examine the potential pitfalls encountered in applying bench discoveries to the bedside as have been learned in the field of septic shock research. PMID:10978715

  1. Involvement of Endoplasmic Reticulum Stress Response in Orofacial Inflammatory Pain

    PubMed Central

    Yang, Eun Sun; Bae, Jin Young; Kim, Tae Heon; Kim, Yun Sook; Suk, Kyoungho

    2014-01-01

    Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2α, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2α immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway. PMID:25548537

  2. Signalling pathways mediating inflammatory responses in brain ischaemia.

    PubMed

    Planas, A M; Gorina, R; Chamorro, A

    2006-12-01

    Stroke causes neuronal necrosis and generates inflammation. Pro-inflammatory molecules intervene in this process by triggering glial cell activation and leucocyte infiltration to the injured tissue. Cytokines are major mediators of the inflammatory response. Pro-inflammatory and anti-inflammatory cytokines are released in the ischaemic brain. Anti-inflammatory cytokines, such as interleukin-10, promote cell survival, whereas pro-inflammatory cytokines, such as TNFalpha (tumour necrosis factor alpha), can induce cell death. However, deleterious effects of certain cytokines can turn to beneficial actions, depending on particular features such as the concentration, time point and the very intricate network of intracellular signals that become activated and interact. A key player in the intracellular response to cytokines is the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway that induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival depending, among other things, on the specific proteins involved. STAT1 activation is related to cell death, whereas STAT3 activation is often associated with survival. Yet, it is clear that STAT activation must be tightly controlled, and for this reason the function of JAK/STAT modulators, such as SOCS (suppressors of cytokine signalling) and PIAS (protein inhibitor of activated STAT), and phosphatases is most relevant. Besides local effects in the ischaemic brain, cytokines are released to the circulation and affect the immune system. Unbalanced pro-inflammatory and anti-inflammatory plasma cytokine concentrations favouring an 'anti-inflammatory' state can decrease the immune response. Robust evidence now supports that stroke can induce an immunodepression syndrome, increasing the risk of infection. The contribution of individual cytokines and their intracellular signalling pathways to this response needs to be further investigated

  3. Local inflammatory response in colorectal cancer.

    PubMed

    Łaskowski, P; Klim, B; Ostrowski, K; Szkudlarek, M; Litwiejko-Pietryńczak, E; Kitlas, K; Nienartowicz, S; Dzięcioł, J

    2016-06-01

    Type and intensity of tumor-infiltrating lymphocytes (TILs) in close proximity to the primary tumor are prognostically significant in postoperative patients. High intensity of TILs is considered to be a prognostically beneficial factor. The research included 66 postoperative colorectal cancer patients. The control group comprised 20 colon segments. Monoclonal antibodies LCA, CD3, CD4, CD5, CD8, CD20, CD23 and CD138 were used to differentiate between T and B lymphocytes. Types of cells in the infiltrate were defined. We found greater numbers of T and B lymphocytes located in close proximity to the cancerous tissue when compared to the control group. T lymphocyte intensity in the inflammatory infiltrations was directly correlated with the size of resected tumors, presence of regional lymphatic node metastases and histological grade of malignancy. Lymphocytic infiltrations of greater intensity located in close proximity to the primary tumor were found in subjects with less advanced colorectal cancer. The research presented here proves direct dependence between the immune system and colorectal cancer. The presence of lymphocytes in the inflammatory infiltrations located in close proximity to the cancerous tissue has been proved to be prognostically beneficial. The obtained results support the application of immunotherapy in colorectal cancer treatment. PMID:27543872

  4. Erythrocyte deformability - A partner of the inflammatory response.

    PubMed

    Silva-Herdade, Ana Santos; Andolina, Giulia; Faggio, Caterina; Calado, Ângelo; Saldanha, Carlota

    2016-09-01

    We aim to establish an in vivo animal model of acute inflammation using PAF (platelet activating factor) as inflammatory agent and to study the erythrocyte deformability changes induced by the inflammatory response. Counting the number of rolling and adherent neutrophils to endothelium after 2, 4 and 6h of intrascrotal injection of PAF we showed the induction of an inflammatory state. Blood samples are collected in order to measure the erythrocyte deformability and to quantify NO efflux from the red blood cells (RBCs). The results show an increased number of rolling and adherent neutrophils after 2h and 4h of inflammation as well as decreased values of erythrocyte deformability in the same time-points. This result is in line with the need of a low blood viscosity to the recruitment process that will improve leukocyte migration towards the endothelial wall. NO efflux from RBCs is also affected by the inflammatory response at the first hours of inflammation. This animal model demonstrates in vivo the association between an acute inflammatory response and the rheological properties of the blood, namely the RBCs deformability. For those reasons we consider this as an adequate model to study acute inflammatory responses as well as hemorheological parameters. PMID:27142964

  5. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    NASA Astrophysics Data System (ADS)

    Borovikova, Lyudmila V.; Ivanova, Svetlana; Zhang, Minghuang; Yang, Huan; Botchkina, Galina I.; Watkins, Linda R.; Wang, Haichao; Abumrad, Naji; Eaton, John W.; Tracey, Kevin J.

    2000-05-01

    Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

  6. Reduced Acute Inflammatory Responses to Microgel Conformal Coatings

    PubMed Central

    Bridges, Amanda W.; Singh, Neetu; Burns, Kellie L.; Babensee, Julia E.; Lyon, L. Andrew; García, Andrés J.

    2008-01-01

    Implantation of synthetic materials into the body elicits inflammatory host responses that limit medical device integration and biological performance. This inflammatory cascade involves protein adsorption, leukocyte recruitment and activation, cytokine release, and fibrous encapsulation of the implant. We present a coating strategy based on thin films of poly(N-isopropylacrylamide) hydrogel microparticles (i.e. microgels) cross-linked with poly(ethylene glycol) diacrylate. These particles were grafted onto a clinically relevant polymeric material to generate conformal coatings that significantly reduced in vitro fibrinogen adsorption and primary human monocytes/macrophage adhesion and spreading. These microgel coatings also reduced leukocyte adhesion and expression of pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) in response to materials implanted acutely in the murine intraperitoneal space. These microgel coatings can be applied to biomedical implants as a protective coating to attenuate biofouling, leukocyte adhesion and activation, and adverse host responses for biomedical and biotechnological applications. PMID:18804859

  7. Supression of inflammatory responses by labdane-type diterpenoids

    SciTech Connect

    Giron, Natalia; Rodriguez, Benjamin; Lopez-Fontal, Raquel; Bosca, Lisardo; Hortelano, Sonsoles Heras, Beatriz de las

    2008-04-15

    A series of 11 labdane-type diterpenoids (1-11) with various patterns of substitution were tested for potential anti-inflammatory activity. Of these compounds, 4 and 11 were selected to evaluate their influence on targets relevant to the regulation of the inflammatory response. These diterpenoids reduced the production of nitric oxide (NO), prostaglandin E2, and tumor necrosis factor-{alpha} in LPS-activated RAW 264.7 macrophages, with IC50 in the range 1-10 {mu}M. Inhibition of these inflammatory mediators was related to inhibition of the expression of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) at the transcriptional level, as determined by western-blot and RT-PCR. Examination of the effects of these diterpenoids on nuclear factor {kappa}B signaling showed that both compounds inhibit the phosphorylation of I{kappa}B{alpha} and I{kappa}B{beta}, preventing their degradation and the nuclear translocation of the NF-{kappa}B p65 subunit. Inhibition of IKK activity was also observed. These derivatives displayed significant anti-inflammatory activity in vivo, suppressing mouse ear edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and inhibiting myeloperoxidase activity, an index of neutrophil infiltration. The anti-inflammatory effects of these labdane diterpenoids, together with their low cell toxicity, suggest potential therapeutic applications in the regulation of the inflammatory response.

  8. Saturated fatty acids trigger TLR4-mediated inflammatory response.

    PubMed

    Rocha, D M; Caldas, A P; Oliveira, L L; Bressan, J; Hermsdorff, H H

    2016-01-01

    Toll-like receptors (TLR) mediate infection-induced inflammation and sterile inflammation by endogenous molecules. Among the TLR family, TLR4 is the best understood. However, while its downstream signaling pathways have been well defined, not all ligands of TLR4 are currently known. Current evidence suggests that saturated fatty acids (SFA) act as non-microbial TLR4 agonists, and trigger its inflammatory response. Thus, our present review provides a new perspective on the potential mechanism by which SFAs could modulate TLR4-induced inflammatory responses: (1) SFAs can be recognized by CD14-TLR4-MD2 complex and trigger inflammatory pathways, similar to lipopolysaccharide (LPS). (2) SFAs lead to modification of gut microbiota with an overproduction of LPS after a high-fat intake, enhancing this natural TLR4 ligand. (3) In addition, this metabolic endotoxemia leads to an oxidative stress thereby producing atherogenic lipids - oxLDL and oxidized phospholipids - which trigger CD36-TLR4-TLR6 inflammatory response. (4) Also, the high SFA consumption increases the lipemia and the mmLDL and oxLDL formation through oxidative modifications of LDL. The mmLDL, unlike oxLDL, is involved in activation of the CD14-TLR4-MD2 inflammatory pathway. Those molecules can induce TLR4 inflammatory response by MyD88-dependent and/or MyD88-independent pathways that, in turn, promotes the expression of proinflammatory transcript factors such as factor nuclear kappa B (NF-κB), which plays a crucial role in the induction of inflammatory mediators (cytokines, chemokines, or costimulatory molecules) implicated in the development and progression of many chronic diseases. PMID:26687466

  9. Sphingosine Kinases Are Not Required for Inflammatory Responses in Macrophages*

    PubMed Central

    Xiong, Yuquan; Lee, Hyeuk Jong; Mariko, Boubacar; Lu, Yi-Chien; Dannenberg, Andrew J.; Haka, Abigail S.; Maxfield, Frederick R.; Camerer, Eric; Proia, Richard L.; Hla, Timothy

    2013-01-01

    Sphingosine kinases (Sphks), which catalyze the formation of sphingosine 1-phosphate (S1P) from sphingosine, have been implicated as essential intracellular messengers in inflammatory responses. Specifically, intracellular Sphk1-derived S1P was reported to be required for NFκB induction during inflammatory cytokine action. To examine the role of intracellular S1P in the inflammatory response of innate immune cells, we derived murine macrophages that lack both Sphk1 and Sphk2 (MΦ Sphk dKO). Compared with WT counterparts, MΦ Sphk dKO cells showed marked suppression of intracellular S1P levels whereas sphingosine and ceramide levels were strongly up-regulated. Cellular proliferation and apoptosis were similar in MΦ Sphk dKO cells compared with WT counterparts. Treatment of WT and MΦ Sphk dKO with inflammatory mediators TNFα or Escherichia coli LPS resulted in similar NFκB activation and cytokine expression. Furthermore, LPS-induced inflammatory responses, mortality, and thioglycolate-induced macrophage recruitment to the peritoneum were indistinguishable between MΦ Sphk dKO and littermate control mice. Interestingly, autophagic markers were constitutively induced in bone marrow-derived macrophages from Sphk dKO mice. Treatment with exogenous sphingosine further enhanced intracellular sphingolipid levels and autophagosomes. Inhibition of autophagy resulted in caspase-dependent cell death. Together, these data suggest that attenuation of Sphk activity, particularly Sphk2, leads to increased intracellular sphingolipids and autophagy in macrophages. PMID:24081141

  10. Mast cells mediate acute inflammatory responses to implanted biomaterials

    PubMed Central

    Tang, Liping; Jennings, Timothy A.; Eaton, John W.

    1998-01-01

    Implanted biomaterials trigger acute and chronic inflammatory responses. The mechanisms involved in such acute inflammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two chemokines—macrophage inflammatory protein 1α/monocyte chemoattractant protein 1—and the phagocyte integrin Mac-1 (CD11b/CD18)/surface fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to biomaterial surfaces. However, it is still not clear how the initial transmigration of phagocytes through the endothelial barrier into the area of the implant is triggered. Because implanted biomaterials elicit histaminic responses in the surrounding tissue, and histamine release is known to promote rapid diapedesis of inflammatory cells, we evaluated the possible role of histamine and mast cells in the recruitment of phagocytes to biomaterial implants. Using i.p. and s.c. implantation of polyethylene terephthalate disks in mice we find: (i) Extensive degranulation of mast cells, accompanied by histamine release, occurs adjacent to short-term i.p. implants. (ii) Simultaneous administration of H1 and H2 histamine receptor antagonists (pyrilamine and famotidine, respectively) greatly diminishes recruitment and adhesion of both neutrophils (<20% of control) and monocytes/macrophages (<30% of control) to implants. (iii) Congenitally mast cell-deficient mice also exhibit markedly reduced accumulation of phagocytes on both i.p. and s.c implants. (iv) Finally, mast cell reconstitution of mast cell-deficient mice restores “normal” inflammatory responses to biomaterial implants. We conclude that mast cells and their granular products, especially histamine, are important in recruitment of inflammatory cells to biomaterial implants. Improved knowledge of such responses may permit purposeful modulation of both acute and chronic inflammation affecting implanted biomaterials. PMID

  11. Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response.

    PubMed

    Hansel, Gisele; Tonon, André Comiran; Guella, Felipe Lhywinskh; Pettenuzzo, Letícia Ferreira; Duarte, Thiago; Duarte, Marta Maria Medeiros Frescura; Oses, Jean Pierre; Achaval, Matilde; Souza, Diogo Onofre

    2015-12-01

    Stroke is the major cause of death and the most frequent cause of disability in the adult population worldwide. Guanosine plays an important neuroprotective role in several cerebral ischemic models and is involved in the modulation of oxidative responses and glutamatergic parameters. Because the excessive reactive oxygen species produced during an ischemic event can trigger an inflammatory response, the purpose of this study was to evaluate the hypothesis that guanosine is neuroprotective against focal cerebral ischemia, inhibits microglia/macrophages activation, and mediates an inflammatory response ameliorating the neural damage. Permanent focal cerebral ischemia was induced in adult rats, and guanosine was administered immediately, 1, 3, and 6 h after surgery. Twenty-four hours after ischemia, the asymmetry scores were evaluated by the cylinder test; neuronal damage was evaluated by Fluoro-Jade C (FJC) staining and propidium iodide (PI) incorporation; microglia and immune cells were evaluated by anti-Iba-1 antibody; and inflammatory parameters such as interleukins (IL): IL-1, IL-6, IL-10; tumor necrosis factors alpha (TNF-α); and interferon-gamma (INF-γ) were evaluated in the brain tissue and cerebrospinal fluid. The ischemic event increased the levels of Iba-1-positive cells and pro-inflammatory cytokines and decreased IL-10 levels (an anti-inflammatory cytokine) in the lesion periphery. The guanosine treatment attenuated the changes in these inflammatory parameters and also reduced the infarct volume, PI incorporation, and number of FJC-positive cells, improving the functional recovery. Thus, guanosine may have been a promising therapeutic agent for the treatment of ischemic brain injury by reduction of inflammatory process triggered in an ischemic event. PMID:25394382

  12. Genomic responses in mouse models poorly mimic human inflammatory diseases

    PubMed Central

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  13. The Pathogenesis of ACLF: The Inflammatory Response and Immune Function.

    PubMed

    Moreau, Richard

    2016-05-01

    Although systemic inflammation is a hallmark of acute-on-chronic liver failure (ACLF), its role in the development of this syndrome is poorly understood. Here the author first summarizes the general principles of the inflammatory response. Inflammation can be triggered by exogenous or endogenous inducers. Important exogenous inducers include bacterial products such as pathogen-associated molecular patterns (PAMPs) and virulence factors. Pathogen-associated molecular patterns elicit inflammation through structural feature recognition (using innate pattern-recognition receptors [PRRs]), whereas virulence factors generally trigger inflammation via functional feature recognition. Endogenous inducers are called danger-associated molecular patterns (DAMPs) and include molecules released by necrotic cells and products of extracellular matrix breakdown. Danger-associated molecular patterns use different PRRs. The purpose of the inflammatory response may differ according to the type of stimulus: The aim of infection-induced inflammation is to decrease pathogen burden, whereas the DAMP-induced inflammation aims to promote tissue repair. An excessive inflammatory response can induce collateral tissue damage (a process called immunopathology). However immunopathology may not be the only mechanism of tissue damage; for example, organ failure can develop because of failed disease tolerance. In this review, the author also discusses how general principles of the inflammatory response can help us to understand the development of ACLF in different contexts: bacterial infection, severe alcoholic hepatitis, and cases in which there is no identifiable trigger. PMID:27172355

  14. Effects of nanoporous alumina on inflammatory cell response.

    PubMed

    Pujari, Shiuli; Hoess, Andreas; Shen, Jinhui; Thormann, Annika; Heilmann, Andreas; Tang, Liping; Karlsson-Ott, Marjam

    2014-11-01

    The present study focuses on the effects of nanoscale porosity on inflammatory response in vitro and in vivo. Nanoporous alumina membranes with different pore sizes, 20 and 200 nm in diameter, were used. We first evaluated cell/alumina interactions in vitro by observing adhesion, proliferation, and activation of a murine fibroblast and a macrophage cell line. To investigate the chronic inflammatory response, the membranes were implanted subcutaneously in mice for 2 weeks. Cell recruitment to the site of implantation was determined by histology and the production of cytokines was measured by protein array analysis. Both in vitro and in vivo studies showed that 200 nm pores induced a stronger inflammatory response as compared to the alumina with 20 nm pores. This was observed by an increase in macrophage activation in vitro as well as higher cell recruitment and generation of proinflammatory cytokines around the alumina with 200 nm pores, in vivo. Our results suggest that nanofeatures can be modulated in order to control the inflammatory response to implants. PMID:24288233

  15. Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses1

    PubMed Central

    Arora, Kamalpreet; Gwinn, William M.; Bower, Molly A.; Watson, Alan; Okwumabua, Ifeanyi; MacDonald, H. Robson; Bukrinsky, Michael I.; Constant, Stephanie L.

    2010-01-01

    The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases. PMID:15972687

  16. COMPARTMENTALIZATION OF THE INFLAMMATORY RESPONSE TO INHALED GRAIN DUST

    EPA Science Inventory


    Interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and the secreted form of the IL-1 receptor antagonist (sIL-1RA) are involved in the inflammatory response to inhaled grain dust. Previously, we found considerable production of these cytokines in the lower...

  17. The choroid plexus response to a repeated peripheral inflammatory stimulus

    PubMed Central

    2009-01-01

    Background Chronic systemic inflammation triggers alterations in the central nervous system that may relate to the underlying inflammatory component reported in neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. However, it is far from being understood whether and how peripheral inflammation contributes to induce brain inflammatory response in such illnesses. As part of the barriers that separate the blood from the brain, the choroid plexus conveys inflammatory immune signals into the brain, largely through alterations in the composition of the cerebrospinal fluid. Results In the present study we investigated the mouse choroid plexus gene expression profile, using microarray analyses, in response to a repeated inflammatory stimulus induced by the intraperitoneal administration of lipopolysaccharide every two weeks for a period of three months; mice were sacrificed 3 and 15 days after the last lipopolysaccharide injection. The data show that the choroid plexus displays a sustained response to the repeated inflammatory stimuli by altering the expression profile of several genes. From a total of 24,000 probes, 369 are up-regulated and 167 are down-regulated 3 days after the last lipopolysaccharide injection, while at 15 days the number decreases to 98 and 128, respectively. The pathways displaying the most significant changes include those facilitating entry of cells into the cerebrospinal fluid, and those participating in the innate immune response to infection. Conclusion These observations contribute to a better understanding of the brain response to peripheral inflammation and pave the way to study their impact on the progression of several disorders of the central nervous system in which inflammation is known to be implicated. PMID:19922669

  18. Titanium surface hydrophilicity modulates the human macrophage inflammatory cytokine response.

    PubMed

    Alfarsi, Mohammed A; Hamlet, Stephen M; Ivanovski, Saso

    2014-01-01

    Increased titanium surface hydrophilicity has been shown to accelerate dental implant osseointegration. Macrophages are important in the early inflammatory response to surgical implant placement and influence the subsequent healing response. This study investigated the modulatory effect of a hydrophilic titanium surface on the inflammatory cytokine expression profile in a human macrophage cell line (THP-1). Genes for 84 cytokines, chemokines, and their receptors were analyzed following exposure to (1) polished (SMO), (2) micro-rough sand blasted, acid etched (SLA), and (3) hydrophilic-modified SLA (modSLA) titanium surfaces for 1 and 3 days. By day 3, the SLA surface elicited a pro-inflammatory response compared to the SMO surface with statistically significant up-regulation of 16 genes [Tumor necrosis factor (TNF) Interleukin (IL)-1β, Chemokine (C-C motif) ligand (CCL)-1, 2, 3, 4, 18, 19, and 20, Chemokine (C-X-C motif) ligand (CXCL)-1, 5, 8 and 12, Chemokine (C-C motif) receptor (CCR)-7, Lymphotoxin-beta (LTB), and Leukotriene B4 receptor (LTB4R)]. This effect was countered by the modSLA surface, which down-regulated the expression of 10 genes (TNF, IL-1α and β, CCL-1, 3, 19 and 20, CXCL-1 and 8, and IL-1 receptor type 1), while two were up-regulated (osteopontin and CCR5) compared to the SLA surface. These cytokine gene expression changes were confirmed by decreased levels of corresponding protein secretion in response to modSLA compared to SLA. These results show that a hydrophilic titanium surface can modulate human macrophage pro-inflammatory cytokine gene expression and protein secretion. An attenuated pro-inflammatory response may be an important molecular mechanism for faster and/or improved wound healing. PMID:23595995

  19. A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo

    PubMed Central

    Vahl, J. Christoph; Aszodi, Attila; Peschke, Katrin; Schenten, Dominik; Hammad, Hamida; Beyaert, Rudi; Saur, Dieter; van Loo, Geert; Roers, Axel; Lambrecht, Bart N.; Kool, Mirjam; Schmidt-Supprian, Marc

    2014-01-01

    Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function. PMID:24453940

  20. Lung epithelial cells modulate the inflammatory response of alveolar macrophages.

    PubMed

    Rubovitch, Vardit; Gershnabel, Shoham; Kalina, Moshe

    2007-12-01

    The goal of this study was to examine the effect of alveolar epithelial cells on inflammatory responses in macrophages. Lung epithelial cells (either rat RLE-6TN or human A549 cells) reduced LPS-induced NO production in alveolar macrophages (AM) in a contact-independent mechanism. The inhibitory effect of the epithelial cells was present already at the transcriptional level: LPS-induced inducible NO synthase (iNOS) expression was significantly smaller. Surfactant protein A (SP-A)-induced NO production by alveolar macrophages was also reduced in the presence of A549 cells, though, by a different kinetics. LPS-induced interleukin-6 (IL-6) production (another inflammatory pathway) by alveolar macrophages was also reduced in the presence of RLE-6TN cells. These data suggest a role for lung epithelial cells in the complicated modulation of inflammatory processes, and provide an insight into the mechanism underlying. PMID:17851743

  1. Janus Kinase-3 Dependent Inflammatory Responses in Allergic Asthma

    PubMed Central

    Malaviya, Rama; Laskin, Debra L.; Malaviya, Ravi

    2010-01-01

    Summary Allergic asthma is a chronic inflammatory condition of the lung characterized by reversible airway obstruction, high serum immunoglobulin (Ig) E levels, and chronic airway inflammation. A number of cells including mast cells, T-cells, macrophages and dendritic cells play a role in the pathogenesis of the disease. Janus Kinase (JAK) −3, a nonreceptor protein tyrosine kinase, traditionally known to mediate cytokine signaling, also regulates functional responses of these cells. In this review the role of JAK-3 in regulating various pathogenic processes in allergic asthma is discussed. We propose that targeting JAK-3 is a rationale approach to control the inflammatory responses of multiple cell types responsible for the pathogenesis of allergic asthma. PMID:20430118

  2. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed Central

    Vieira, Mônica L.; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C.; Nascimento, Ana Lucia T. O.; Herwald, Heiko

    2016-01-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  3. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    PubMed

    Vieira, Mônica L; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C; Nascimento, Ana Lucia T O; Herwald, Heiko

    2016-05-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  4. The Systemic Inflammatory Response to Clostridium difficile Infection

    PubMed Central

    Rao, Krishna; Erb-Downward, John R.; Walk, Seth T.; Micic, Dejan; Falkowski, Nicole; Santhosh, Kavitha; Mogle, Jill A.; Ring, Cathrin; Young, Vincent B.; Huffnagle, Gary B.; Aronoff, David M.

    2014-01-01

    Background The systemic inflammatory response to Clostridium difficile infection (CDI) is incompletely defined, particularly for patients with severe disease. Methods Analysis of 315 blood samples from 78 inpatients with CDI (cases), 100 inpatients with diarrhea without CDI (inpatient controls), and 137 asymptomatic outpatient controls without CDI was performed. Serum or plasma was obtained from subjects at the time of CDI testing or shortly thereafter. Severe cases had intensive care unit admission, colectomy, or death due to CDI within 30 days after diagnosis. Thirty different circulating inflammatory mediators were quantified using an antibody-linked bead array. Principal component analysis (PCA), multivariate analysis of variance (MANOVA), and logistic regression were used for analysis. Results Based on MANOVA, cases had a significantly different inflammatory profile from outpatient controls but not from inpatient controls. In logistic regression, only chemokine (C-C motif) ligand 5 (CCL5) levels were associated with cases vs. inpatient controls. Several mediators were associated with cases vs. outpatient controls, especially hepatocyte growth factor, CCL5, and epithelial growth factor (inversely associated). Eight cases were severe and associated with elevations in IL-8, IL-6, and eotaxin. Conclusions A broad systemic inflammatory response occurs during CDI and severe cases appear to differ from non-severe infections. PMID:24643077

  5. Filoviruses and the balance of innate, adaptive, and inflammatory responses.

    PubMed

    Mohamadzadeh, Mansour; Chen, Lieping; Olinger, Gene G; Pratt, William D; Schmaljohn, Alan L

    2006-01-01

    The Filoviruses Marburg virus and Ebola virus are among the deadliest of human pathogens, causing fulminant hemorrhagic fevers typified by overmatched specific immune responses and profuse inflammatory responses. Keys to both vaccination and treatment may reside, first, in the understanding of immune dysfunctions that parallel Filoviral disease and, second, in devising ways to redirect and restore normal immune function as well as to mitigate inflammation. Here, we describe how Filoviral infections may subvert innate immune responses through perturbances of dendritic cells and neutrophils, with particular emphasis on the downstream effects on adaptive immunity and inflammation. We suggest that pivotal events may be subject to therapeutic intervention as Filoviruses encounter immune processes. PMID:17201655

  6. Benfotiamine Attenuates Inflammatory Response in LPS Stimulated BV-2 Microglia

    PubMed Central

    Bozic, Iva; Savic, Danijela; Laketa, Danijela; Bjelobaba, Ivana; Milenkovic, Ivan; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

    2015-01-01

    Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may

  7. Inflammatory Responses to Salmonella Infections Are Serotype-Specific

    PubMed Central

    Ktsoyan, Zhanna; Ghazaryan, Karine; Manukyan, Gayane; Martirosyan, Anush; Mnatsakanyan, Armine; Arakelova, Karine; Gevorgyan, Zaruhi; Sedrakyan, Anahit; Asoyan, Ara; Boyajyan, Anna; Aminov, Rustam

    2013-01-01

    The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage. PMID:26904722

  8. Inflammatory Responses to Salmonella Infections Are Serotype-Specific.

    PubMed

    Ktsoyan, Zhanna; Ghazaryan, Karine; Manukyan, Gayane; Martirosyan, Anush; Mnatsakanyan, Armine; Arakelova, Karine; Gevorgyan, Zaruhi; Sedrakyan, Anahit; Asoyan, Ara; Boyajyan, Anna; Aminov, Rustam

    2013-01-01

    The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage. PMID:26904722

  9. Th2 and eosinophil responses suppress inflammatory arthritis

    PubMed Central

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2–eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2–eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  10. Th2 and eosinophil responses suppress inflammatory arthritis.

    PubMed

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  11. The role of peroxiredoxin 4 in inflammatory response and aging.

    PubMed

    Klichko, Vladimir I; Orr, William C; Radyuk, Svetlana N

    2016-02-01

    In prior studies, we determined that the moderate overexpression of the Drosophila endoplasmic reticulum (ER)-localized peroxiredoxin (Prx), dPrx4, reduced oxidative damage and conferred beneficial effects on life span, while a high-level expression increased the incidence of tissue-specific apoptosis and dramatically shortened longevity. The detrimental pro-apoptotic and life-shortening effects were attributed to aberrant localization of dPrx4 and the apparent ER stress elicited by dPrx4 overexpression. In addition, the activation of both the NF-κB- and the JAK/STAT-mediated stress responses was detected, although it was not clear whether these served as functional alarm signals. Here we extend these findings to show that the activation of the NF-κB-dependent immunity-related/inflammatory genes, associated with life span shortening effects, is dependent on the activity of a Drosophila NF-κB ortholog, Relish. In the absence of Relish, the pro-inflammatory effects typically elicited by dPrx4 overexpression were not detected. The absence of Relish not only prevented the hyperactivation of the immunity-related genes but also significantly rescued the severe shortening of life span normally observed in dPrx4 overexpressors. The overactivation of the immune/inflammatory responses was also lessened by JAK/STAT signaling. In addition, we found that cellular immune/pro-inflammatory responses provoked by the oxidant paraquat but not bacteria are mediated via dPrx4 activity in the ER, as the upregulation of the immune-related genes was eliminated in flies underexpressing dPrx4, whereas immune responses triggered by bacteria were unaffected. Finally, efforts to reveal critical tissues where dPrx4 modulates longevity showed that broad targeting of dPrx4 to neuronal tissue had strong beneficial effects, while targeting expression to the fat body had deleterious effects. PMID:26689888

  12. Engineering macrophages to control the inflammatory response and angiogenesis.

    PubMed

    Eaton, K V; Yang, H L; Giachelli, C M; Scatena, M

    2015-12-10

    Macrophage (MΦ) dysregulation is increasingly becoming recognized as a risk factor for a number of inflammatory complications including atherosclerosis, cancer, and the host response elicited by biomedical devices. It is still unclear what roles the pro-inflammatory (M1) MΦ and pro-healing (M2) MΦ phenotypes play during the healing process. However, it has been shown that a local overabundance of M1 MΦs can potentially lead to a chronically inflamed state of the tissue; while a local over-exuberant M2 MΦ response can lead to tissue fibrosis and even promote tumorigenesis. These notions strengthen the argument that the tight temporal regulation of this phenotype balance is necessary to promote inflammatory resolution that leads to tissue homeostasis. In this study, we have engineered pro-inflammatory MΦs, MΦ-cTLR4 cells, which can be activated to a M1-like MΦ phenotype with a small molecule, the chemical inducer of dimerization (CID) drug. The MΦ-cTLR4 cells when activated with the CID drug, express increased levels of TNFα, IL-6, and iNOS. Activated MΦ-cTLR4 cells stay stimulated for at least 48h; once the CID drug is withdrawn, the MΦ-cTLR4 cells return to baseline state within 18h. Further, in vitro CID-activated MΦ-cTLR4 cells induce upregulation of VCAM-1 and ICAM-1 on endothelial cells (EC) in a TNFα-dependent manner. With the ability to specifically modulate the MФ-cTLR4 cells with the presence or absence of a small molecule, we now have the tool necessary to observe a primarily M1 MФ response during inflammation. By isolating this phase of the wound healing response, it may be possible to determine conditions for ideal healing. PMID:26610863

  13. Post-mating inflammatory responses of the uterus.

    PubMed

    Katila, T

    2012-08-01

    This review attempts to summarize the current knowledge on uterine inflammatory response after mating in horses, pigs and cattle. Post-mating endometritis has been extensively studied in horses as it has been considered to cause infertility. The inflammation is known to occur also in cattle, but it has not been investigated to a similar extent. There are a number of publications about mechanisms of post-mating uterine inflammation in pigs, which seem to resemble those in horses. The major focus of this review is the horse, but relevant literature is presented also on swine and cattle. Spermatozoa, seminal plasma and semen extenders play roles in the induction of inflammation. In addition, sperm numbers, concentration and viability, as well as the site of semen deposition may modulate the inflammatory response. Cytokines, polymorphonuclear leucocytes (PMN) and mononuclear cells represent the uterine inflammatory response to mating. Inflammation is the first line of defence against invasion and eliminates excess spermatozoa and bacteria. Semen deposition elicits a massive PMN invasion, followed by phagocytosis of sperm aided by the formation of neutrophil extracellular traps. Exposure of the female genital tract to semen is important also for endometrial receptivity and pre-implantation embryo development. Seminal plasma (SP) and inflammation elicit transient immune tolerance to antigens present in semen. SP contains immune-regulatory molecules that activate and control immune responses to antigens by stimulating expression of cytokines and growth factors and by initiating tissue remodelling. SP also regulates ovarian function. Effective elimination of excess sperm and inflammatory by-products and subsequent rapid return of the endometrium to the normal state is a prerequisite for pregnancy. Uterine backflow, driven by myometrial contractions and requiring a patent cervix, is an important physical tool in uterine drainage. PMID:22913558

  14. Innate immune inflammatory response in the acutely ischemic myocardium.

    PubMed

    Deftereos, Spyridon; Angelidis, Christos; Bouras, Georgios; Raisakis, Konstantinos; Gerckens, Ulrich; Cleman, Michael W; Giannopoulos, Georgios

    2014-01-01

    The "holy grail" of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous 'danger' signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing. PMID:25102201

  15. Inflammatory responses in Ebola virus-infected patients

    PubMed Central

    BAIZE, S; LEROY, E M; GEORGES, A J; GEORGES-COURBOT, M-C; CAPRON, M; BEDJABAGA, I; LANSOUD-SOUKATE, J; MAVOUNGOU, E

    2002-01-01

    Ebola virus subtype Zaire (Ebo-Z) induces acute haemorrhagic fever and a 60–80% mortality rate in humans. Inflammatory responses were monitored in victims and survivors of Ebo-Z haemorrhagic fever during two recent outbreaks in Gabon. Survivors were characterized by a transient release in plasma of interleukin-1β (IL-1β), IL-6, tumour necrosis factor-α (TNFα), macrophage inflammatory protein-1α (MIP-1α) and MIP-1β early in the disease, followed by circulation of IL-1 receptor antagonist (IL-1RA) and soluble receptors for TNFα (sTNF-R) and IL-6 (sIL-6R) towards the end of the symptomatic phase and after recovery. Fatal infection was associated with moderate levels of TNFα and IL-6, and high levels of IL-10, IL-1RA and sTNF-R, in the days before death, while IL-1β was not detected and MIP-1α and MIP-1β concentrations were similar to those of endemic controls. Simultaneous massive activation of monocytes/macrophages, the main target of Ebo-Z, was suggested in fatal infection by elevated neopterin levels. Thus, presence of IL-1β and of elevated concentrations of IL-6 in plasma during the symptomatic phase can be used as markers of non-fatal infection, while release of IL-10 and of high levels of neopterin and IL-1RA in plasma as soon as a few days after the disease onset is indicative of a fatal outcome. In conclusion, recovery from Ebo-Z infection is associated with early and well-regulated inflammatory responses, which may be crucial in controlling viral replication and inducing specific immunity. In contrast, defective inflammatory responses and massive monocyte/macrophage activation were associated with fatal outcome. PMID:11982604

  16. On the inflammatory response in metal-on-metal implants

    PubMed Central

    2014-01-01

    Background Metal-on-metal implants are a special form of hip endoprostheses that despite many advantages can entail serious complications due to release of wear particles from the implanted material. Metal wear particles presumably activate local host defence mechanisms, which causes a persistent inflammatory response with destruction of bone followed by a loosening of the implant. To better characterize this inflammatory response and to link inflammation to bone degradation, the local generation of proinflammatory and osteoclast-inducing cytokines was analysed, as was systemic T cell activation. Methods By quantitative RT-PCR, gene expression of cytokines and markers for T lymphocytes, monocytes/macrophages and osteoclasts, respectively, was analysed in tissue samples obtained intraoperatively during exchange surgery of the loosened implant. Peripheral T cells were characterized by cytofluorometry before surgery and 7 to 10 days thereafter. Results At sites of osteolysis, gene expression of cathepsin K, CD14 and CD3 was seen, indicating the generation of osteoclasts, and the presence of monocytes and of T cells, respectively. Also cytokines were highly expressed, including CXCL8, IL-1ß, CXCL2, MRP-14 and CXCL-10. The latter suggest T cell activation, a notion that could be confirmed by detecting a small, though conspicuous population of activated CD4+ cells in the peripheral blood T cells prior to surgery. Conclusion Our data support the concept that metallosis is the result of a local inflammatory response, which according to histomorphology and the composition of the cellular infiltrate classifies as an acute phase of a chronic inflammatory disease. The proinflammatory environment, particularly the generation of the osteoclast-inducing cytokines CXCL8 and IL1-ß, promotes bone resorption. Loss of bone results in implant loosening, which then causes the major symptoms of metallosis, pain and reduced range of motion. PMID:24650243

  17. Inflammatory biomarkers as differential predictors of antidepressant response.

    PubMed

    Hashimoto, Kenji

    2015-01-01

    Although antidepressants are generally effective in the treatment of major depressive disorder (MDD), it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. PMID:25856677

  18. Defining the Systemic Inflammatory Response Syndrome in Equine Neonates.

    PubMed

    Wong, David M; Wilkins, Pamela A

    2015-12-01

    Defining and describing the systemic inflammatory response syndrome (SIRS) and sepsis facilitated recognition and investigation of the complex disease processes involving the host response to infection and trauma. Over the years a variety of definitions of SIRS have been examined and applied to numerous research studies to improve critical care in both human and veterinary clinical practice. This article summarizes the history of the development of the SIRS definition, outlines the pathophysiologic processes that are involved in SIRS, and provides a specific definition for use in foal medicine. PMID:26612743

  19. Human Monoclonal Antibodies against Clostridium difficile Toxins A and B Inhibit Inflammatory and Histologic Responses to the Toxins in Human Colon and Peripheral Blood Monocytes

    PubMed Central

    Koon, Hon Wai; Shih, David Q.; Hing, Tressia C.; Yoo, Jun Hwan; Ho, Samantha; Chen, Xinhua; Kelly, Ciarán P.; Targan, Stephan R.

    2013-01-01

    Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI. Recent studies indicated that human monoclonal antibodies (MAbs) against toxins A and B reduce their cytotoxic and secretory activities and prevent CDI in hamsters. Moreover, anti-toxin A and anti-toxin B MAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these MAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocyte cells (PBMCs) has never been examined. We used fresh human colonic biopsy specimens and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling, and histologic damage. Incubation of anti-toxin A (MK3415) or anti-toxin B (MK6072) MAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) expression. MK3415 and MK6072 also diminished toxin A- and toxin B-mediated NF-κB p65 phosphorylation in human monocytes, respectively, and significantly reduced toxin A- and B-induced TNF-α and IL-1β expression as well as histologic damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B-mediated inflammatory responses and histologic damage. PMID:23629713

  20. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  1. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity.

    PubMed

    Cover, Cathleen; Liu, Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P; Bajt, Mary Lynn; Jaeschke, Hartmut

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-alpha, interleukin-1beta and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose. PMID:16781746

  2. The Inflammatory Response in Psoriasis: a Comprehensive Review.

    PubMed

    Deng, Yaxiong; Chang, Christopher; Lu, Qianjin

    2016-06-01

    Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis. PMID:27025861

  3. Role of moesin in HMGB1-stimulated severe inflammatory responses.

    PubMed

    Lee, W; Kwon, O K; Han, M-S; Lee, Y-M; Kim, S-W; Kim, K-M; Lee, T; Lee, S; Bae, J-S

    2015-08-01

    Sepsis is a life-threatening condition that arises when the body's response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyperpermeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and paracellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis. PMID:25947626

  4. Immunological and Inflammatory Responses to Organic Dust in Agriculture

    PubMed Central

    Poole, Jill A.; Romberger, Debra J.

    2012-01-01

    Purpose of review Agriculture represents a major industry worldwide, and despite protection against the development of IgE-mediated diseases, chronic exposure to agriculture-related organic dusts is associated with an increased risk of developing respiratory disease. This article will review the literature regarding new knowledge of important etiologic agents in the dusts and focus on the immunologic responses following acute and repetitive organic dust exposures. Recent findings Although endotoxin remains important, there is an emerging role for non-endotoxin components such as peptidoglycans from Gram-positive bacteria. Pattern recognition receptors including Toll-like receptor 4 (TLR4), TLR2 and intracellular nucleotide oligomerization domain-like receptors are partially responsible for mediating the inflammatory consequences. Repeated organic dust exposures modulate innate and adaptive immune function with a resultant adaptation-like response. However, repetitive exposures cause lung parenchymal inflammation, chronic disease, and lung function decline over time. Summary The immunological consequences of organic dust exposure in the farming industry are likely explained by the diversity of microbial motifs in dust that can elicit differing innate immune receptor signaling pathways. Whereas initial activation results in a robust inflammatory response, repetitive dust exposures modulate immunity. This can result in low-grade, chronic inflammation and/or protection against allergic disease. PMID:22306554

  5. Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion.

    PubMed

    Anthony, Scott M; Rivas, Sarai C; Colpitts, Sara L; Howard, Megan E; Stonier, Spencer W; Schluns, Kimberly S

    2016-06-01

    Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG(-/-) mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on type I IFNs. The stimulator of IFN genes pathway was discovered to be a potent inducer of sIL-15 complexes and was required for optimal production of sIL-15 complexes in response to Ab-mediated T cell depletion and TBI, suggesting products of cell death drive production of sIL-15 complexes after lymphodepletion. Lastly, we provide evidence that IL-15 induced by inflammatory signals in response to lymphodepletion drives lymphocyte responses, as memory CD8 T cells proliferated in an IL-15-dependent manner. Overall, these studies demonstrate that the form in which IL-15 is expressed, its kinetics and cellular sources, and the inflammatory signals involved are differentially dictated by the manner in which lymphopenia is induced. PMID:27183627

  6. Systemic inflammatory responses in African tick-bite fever.

    PubMed

    Jensenius, Mogens; Ueland, Thor; Fournier, Pierre-Edouard; Brosstad, Frank; Stylianou, Eva; Vene, Sirkka; Myrvang, Bjørn; Raoult, Didier; Aukrust, Pål

    2003-04-15

    Information regarding the inflammatory response in African tick-bite fever (ATBF), an emerging spotted-fever-group rickettsiosis, in international travelers to sub-Saharan Africa, is scarce. Plasma/serum levels of von Willebrand factor (vWF), soluble (s) E-selectin, tumor necrosis factor-alpha, interleukin (IL)-6, interferon-gamma, IL-10, IL-13, IL-8, RANTES, macrophage inflammatory protein-1alpha, and C-reactive protein were studied, at both first presentation and follow-up, in 15 patients with travel-associated ATBF and in 14 healthy travelers who served as control subjects. Our main and novel findings are the following: (1) patients with ATBF had increased levels of vWF and sE-selectin, with a subsequent decrease at follow-up; (2) with the exception of IFN-gamma, levels of cytokines and chemokines were also increased in these patients at the first presentation; and (3) IL-10 and IL-13 tended to increase during follow-up, whereas most of the inflammatory cytokines decreased. The induction of these mediators and the balance between them may be critical both for the regulation of inflammation and for protective immunity in ATBF. PMID:12696016

  7. Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases.

    PubMed

    Middleton, Elizabeth A; Weyrich, Andrew S; Zimmerman, Guy A

    2016-10-01

    Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury. PMID:27489307

  8. The hepatic inflammatory response after acetaminophen overdose: role of neutrophils.

    PubMed

    Lawson, J A; Farhood, A; Hopper, R D; Bajt, M L; Jaeschke, H

    2000-04-01

    Acetaminophen overdose induces severe liver injury and hepatic failure. There is evidence that inflammatory cells may be involved in the pathophysiology. Thus, the aim of this investigation was to characterize the neutrophilic inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen. A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The number of neutrophils in the liver was substantial (209 +/- 64 PMN/50 high-power fields at 12 h) compared to baseline levels (7 +/- 1). Serum levels of TNF-alpha and the C-X-C chemokines KC and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in controls during the injury process. In addition, mRNA expression of MIP-2 and KC were upregulated in livers of acetaminophen-treated animals as determined by ribonuclease protection assay. However, none of these mediators were generated in large enough quantities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on circulating neutrophils. Moreover, an anti-CD18 antibody had no protective effect against acetaminophen overdose during the first 24 h. These results indicate that there is a local inflammatory response after acetaminophen overdose, including a substantial accumulation of neutrophils in the liver. Because of the critical importance of beta2 integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver. The inflammation observed after acetaminophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe enough to cause additional damage. PMID:10774834

  9. Scutellarein Reduces Inflammatory Responses by Inhibiting Src Kinase Activity

    PubMed Central

    Sung, Nak Yoon

    2015-01-01

    Flavonoids are plant pigments that have been demonstrated to exert various pharmacological effects including anti-cancer, anti-diabetic, anti-atherosclerotic, anti-bacterial, and anti-inflammatory activities. However, the molecular mechanisms in terms of exact target proteins of flavonoids are not fully elucidated yet. In this study, we aimed to evaluate the anti-inflammatory mechanism of scutellarein (SCT), a flavonoid isolated from Erigeron breviscapus, Clerodendrum phlomidis and Oroxylum indicum Vent that have been traditionally used to treat various inflammatory diseases in China and Brazil. For this purpose, a nitric oxide (NO) assay, polymerase chain reaction (PCR), nuclear fractionation, immunoblot analysis, a kinase assay, and an overexpression strategy were employed. Scutellarein significantly inhibited NO production in a dose-dependent manner and reduced the mRNA expression levels of inducible NO synthase (iNOS) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-activated RAW264.7 cells. In addition, SCT also dampened nuclear factor (NF)-κB-driven expression of a luciferase reporter gene upon transfection of a TIR-domain-containing adapter-inducing interferon-β (TRIF) construct into Human embryonic kidney 293 (HEK 293) cells; similarly, NF-κ B nuclear translocation was inhibited by SCT. Moreover, the phosphorylation levels of various upstream signaling enzymes involved in NF-κB activation were decreased by SCT treatment in LPS-treated RAW264.7 cells. Finally, SCT strongly inhibited Src kinase activity and also inhibited the autophosphorylation of overexpressed Src. Therefore, our data suggest that SCT can block the inflammatory response by directly inhibiting Src kinase activity linked to NF-κB activation. PMID:26330757

  10. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis

    PubMed Central

    Lu, Ching-Hua; Allen, Kezia; Oei, Felicia; Leoni, Emanuela; Kuhle, Jens; Tree, Timothy; Fratta, Pietro; Sharma, Nikhil; Sidle, Katie; Howard, Robin; Orrell, Richard; Fish, Mark; Greensmith, Linda; Pearce, Neil; Gallo, Valentina

    2016-01-01

    Objective: To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS). Methods: Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS. Results: Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)–α, and interleukin (IL)–1β, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)–γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis. Conclusions: Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS. PMID:27308305

  11. Attachment avoidance predicts inflammatory responses to marital conflict.

    PubMed

    Gouin, Jean-Philippe; Glaser, Ronald; Loving, Timothy J; Malarkey, William B; Stowell, Jeffrey; Houts, Carrie; Kiecolt-Glaser, Janice K

    2009-10-01

    Marital stress has been associated with immune dysregulation, including increased production of interleukin-6 (IL-6). Attachment style, one's expectations about the availability and responsiveness of others in intimate relationships, appears to influence physiological stress reactivity and thus could influence inflammatory responses to marital conflict. Thirty-five couples were invited for two 24-h admissions to a hospital research unit. The first visit included a structured social support interaction, while the second visit comprised the discussion of a marital disagreement. A mixed effect within-subject repeated measure model indicated that attachment avoidance significantly influenced IL-6 production during the conflict visit but not during the social support visit. Individuals with higher attachment avoidance had on average an 11% increase in total IL-6 production during the conflict visit as compared to the social support visit, while individuals with lower attachment avoidance had, on average, a 6% decrease in IL-6 production during the conflict visit as compared to the social support visit. Furthermore, greater attachment avoidance was associated with a higher frequency of negative behaviors and a lower frequency of positive behaviors during the marital interaction, providing a mechanism by which attachment avoidance may influence inflammatory responses to marital conflict. In sum, these results suggest that attachment avoidance modulates marital behavior and stress-induced immune dysregulation. PMID:18952163

  12. Effects of tityustoxin on cerebral inflammatory response in young rats.

    PubMed

    Van Fraga, Iva Tereza; Limborço-Filho, Marcelo; Lima, Onésia Cristina Oliveira; Lacerda-Queiroz, Norinne; Guidine, Patrícia Alves Maia; Moraes, Márcio Flávio Dutra; Nascimento Araújo, Ricardo; Moraes-Santos, Tasso; Massensini, André Ricardo; Arantes, Rosa Maria Esteves; Carvalho-Tavares, Juliana

    2015-02-19

    Accidents caused by scorpion stings, mainly affecting children, are considered an important cause of morbidity and mortality in tropical countries. Clinical studies demonstrate the relevant role of systemic inflammatory events in scorpion envenoming. However, remains poorly understood whether the major lethal component in Tityus serrulatus venom, tityustoxin (TsTX), is able to induce inflammatory responses in the cerebral microcirculation. In this study, we systematically examined leukocyte recruitment into the CNS in response to TsTX injection. Accordingly, developing rats were subjected to a subcutaneous (s.c.) injection of TsTX (0.75mg/kg), and leukocyte recruitment (i.e., 4, 8 and 12h after injection) and TNF-α levels were evaluated. Rats injected with TsTX presented a significant increase in leukocyte rolling and adhesion and higher levels of TNF-α at all time points studied, compared to the control group. Altogether, this work demonstrates the triggering of neuroimmunological mechanisms induced by TsTX injection in young rats. PMID:25545555

  13. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis

    PubMed Central

    Segura-Cervantes, Enrique; Mancilla-Ramírez, Javier; González-Canudas, Jorge; Alba, Erika; Santillán-Ballesteros, René; Morales-Barquet, Deneb; Sandoval-Plata, Gabriela

    2016-01-01

    The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. PMID:27293317

  14. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis.

    PubMed

    Segura-Cervantes, Enrique; Mancilla-Ramírez, Javier; González-Canudas, Jorge; Alba, Erika; Santillán-Ballesteros, René; Morales-Barquet, Deneb; Sandoval-Plata, Gabriela; Galindo-Sevilla, Norma

    2016-01-01

    The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. PMID:27293317

  15. Rosiglitazone inhibits chlorpyrifos-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells

    SciTech Connect

    Lee, Jeong Eun; Park, Jae Hyeon; Jang, Sea Jeong; Koh, Hyun Chul

    2014-07-15

    Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-κB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, against CPF-induced neuronal cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-α. CPF also induced nuclear translocation of NF-κB and inhibitors of NF-κB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-κB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-κB. - Highlights: • CPF induces apoptotic cell death in SH-SY5Y cells • ROS involved in CPF-mediated apoptotic cell death • Inflammation involved in CPF-mediated apoptotic cell death • Rosiglitazone modulates ROS and inflammatory response in CPF-treated cells.

  16. Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.

    PubMed

    Saia, Rafael Simone; Bertozi, Giuliana; Mestriner, Fabíola Leslie; Antunes-Rodrigues, José; Queiróz Cunha, Fernando; Cárnio, Evelin Capellari

    2013-01-01

    Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function. PMID:23247127

  17. Biotin deficiency enhances the inflammatory response of human dendritic cells.

    PubMed

    Agrawal, Sudhanshu; Agrawal, Anshu; Said, Hamid M

    2016-09-01

    The water-soluble biotin (vitamin B7) is indispensable for normal human health. The vitamin acts as a cofactor for five carboxylases that are critical for fatty acid, glucose, and amino acid metabolism. Biotin deficiency is associated with various diseases, and mice deficient in this vitamin display enhanced inflammation. Previous studies have shown that biotin affects the functions of adaptive immune T and NK cells, but its effect(s) on innate immune cells is not known. Because of that and because vitamins such as vitamins A and D have a profound effect on dendritic cell (DC) function, we investigated the effect of biotin levels on the functions of human monocyte-derived DCs. Culture of DCs in a biotin-deficient medium (BDM) and subsequent activation with LPS resulted in enhanced secretion of the proinflammatory cytokines TNF-α, IL-12p40, IL-23, and IL-1β compared with LPS-activated DCs cultured in biotin-sufficient (control) and biotin-oversupplemented media. Furthermore, LPS-activated DCs cultured in BDM displayed a significantly higher induction of IFN-γ and IL-17 indicating Th1/Th17 bias in T cells compared with cells maintained in biotin control or biotin-oversupplemented media. Investigations into the mechanisms suggested that impaired activation of AMP kinase in DCs cultured in BDM may be responsible for the observed increase in inflammatory responses. In summary, these results demonstrate for the first time that biotin deficiency enhances the inflammatory responses of DCs. This may therefore be one of the mechanism(s) that mediates the observed inflammation that occurs in biotin deficiency. PMID:27413170

  18. Fracture initiates systemic inflammatory response syndrome through recruiting polymorphonuclear leucocytes.

    PubMed

    Li, Haipeng; Liu, Jia; Yao, Jianhua; Zhong, Jianfeng; Guo, Lei; Sun, Tiansheng

    2016-08-01

    Fracture, a common type injury in trauma patients, often results in the development of the systemic inflammatory response syndrome (SIRS). Though the mechanism of the fracture-initiated SIRS still remains not well characterized, it is well documented that the polymorphonuclear leucocytes (PMN) play an important role in the inflammatory process. We hypothesize that fractures recruit PMN to the local tissue, which is followed by an increase in the number of peripheral PMN and initiation of SIRS. In the current study, we established a closed femoral fracture rat model. We evaluated the levels of MPO, IL-1β and CINC-1 in fractured tissue homogenate, and we measured the levels of IL-6 and IL-10, the biomarkers for systemic inflammatory response, in the rat sera. In clinical part of the study, we collected blood from patients with isolated closed femoral fractures and evaluated PMN-related chemoattractants (IL-8, IL-1β and G-CSF) and the number of peripheral PMN. We further evaluated the level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of the patients with fracture. In the animal model of closed femoral fracture, we found a significant recruitment of PMN to the local tissue after fracture, which correlates with the elevated MPO level. We also showed that the concentration of IL-1β and CINC-1 in local tissue is significantly increased and might be responsible for the PMN recruitment. Recruitment of PMN to the local tissue was accompanied with a significant increase in the systemic levels of IL-6 and IL-10 in serum. In the patients with closed femoral fracture, we observed an increase in the number of peripheral PMN and PMN-related chemoattractants, including IL-8, IL-1β and G-CSF. The level of mitochondrial DNA in the local haematoma of fracture and the circulating plasma of patients were significantly higher compared to the healthy volunteers. Our data suggest that fracture released mitochondrial DNA into the local haematoma of

  19. Hyaluronidase Modulates Inflammatory Response and Accelerates the Cutaneous Wound Healing

    PubMed Central

    Fronza, Marcio; Caetano, Guilherme F.; Leite, Marcel N.; Bitencourt, Claudia S.; Paula-Silva, Francisco W. G.; Andrade, Thiago A. M.; Frade, Marco A. C.; Merfort, Irmgard; Faccioli, Lúcia H.

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  20. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

    PubMed Central

    Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

    2014-01-01

    Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

  1. Hyaluronidase modulates inflammatory response and accelerates the cutaneous wound healing.

    PubMed

    Fronza, Marcio; Caetano, Guilherme F; Leite, Marcel N; Bitencourt, Claudia S; Paula-Silva, Francisco W G; Andrade, Thiago A M; Frade, Marco A C; Merfort, Irmgard; Faccioli, Lúcia H

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  2. Toll-like receptor 4 confers inflammatory response to Suilysin

    PubMed Central

    Bi, Lili; Pian, Yaya; Chen, Shaolong; Ren, Zhiqiang; Liu, Peng; Lv, Qingyu; Zheng, Yuling; Zhang, Shengwei; Hao, Huaijie; Yuan, Yuan; Jiang, Yongqiang

    2015-01-01

    Streptococcus suis serotype 2 (SS2) is an emerging human pathogen worldwide. A large outbreak occurred in the summer of 2005 in China. Serum samples from this outbreak revealed that levels of the main proinflammatory cytokines were significantly higher in patients with streptococcal toxic-shock-like syndrome (STSLS) than in patients with meningitis only. However, the mechanism underlying the cytokine storm in STSLS caused by SS2 remained unclear. In this study, we found that suilysin (SLY) is the main protein inflammatory stimulus of SS2 and that native SLY (nSLY) stimulated cytokines independently of its haemolytic ability. Interestingly, a small amount of SLY (Å Mol/L) induced strong, long-term TNF-α release from human PBMCs. We also found that nSLY stimulated TNF-α in wild-type macrophages but not in macrophages from mice that carried a spontaneous mutation in TLR4 (P712H). We demonstrated for the first time that SLY stimulates immune cells through TLR4. In addition, the Myd88 adaptor-p38-MAPK pathway was involved in this process. The present study suggested that the TLR4-dependent inflammatory responses induced by SLY in host might contribute to the STSLS caused by SS2 and that p38-MAPK could be used as a target to control the release of excess TNF-α induced by SS2. PMID:26167160

  3. Biomechanical changes in endothelial cells result from an inflammatory response

    NASA Astrophysics Data System (ADS)

    Vaitkus, Janina; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    During periods of infection and disease, the immune system induces the release of TNF-α, an inflammatory cytokine, from a variety of cell types, such as macrophages. TNF-α, while circulating in the vasculature, binds to the apical surface of endothelial cells and causes a wide range of biological and mechanical changes to the endothelium. While the biological changes have been widely studied, the biomechanical aspects have been largely unexplored. Here, we investigated the biomechanical changes of the endothelium as a function of TNF-α treatment. First, we studied the traction forces applied by the endothelium, an effect that is much less studied than others. Through the use of traction force microscopy, we found that TNF-α causes an increase in traction forces applied by the endothelial cells as compared to non-treated cells. Then, we investigated cell morphology, cell mechanics, migration, and cytoskeletal dynamics. We found that in addition to increasing applied traction forces, TNF-α causes an increase in cell area and aspect ratio on average, as well as a shift in the organization of F-actin filaments within the cell. Combining these findings together, our results show that an inflammatory response heavily impacts the morphology, cell mechanics, migration, cytoskeletal dynamics, and applied traction forces of endothelial cells.

  4. The Role of Protein Arginine Methyltransferases in Inflammatory Responses

    PubMed Central

    Kim, Ji Hye; Yoo, Byong Chul; Yang, Woo Seok; Kim, Eunji; Hong, Sungyoul

    2016-01-01

    Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I–IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required. Inflammation is an essential defense reaction of the body to eliminate harmful stimuli, including damaged cells, irritants, or pathogens. However, chronic inflammation can eventually cause several types of diseases, including some cancers, atherosclerosis, rheumatoid arthritis, and periodontitis. Therefore, inflammation responses should be well modulated. In this review, we briefly discuss the role of PRMTs in the control of inflammation. More specifically, we review the roles of four PRMTs (CARM1, PRMT1, PRMT5, and PRMT6) in modulating inflammation responses, particularly in terms of modulating the transcriptional factors or cofactors related to inflammation. Based on the regulatory roles known so far, we propose that PRMTs should be considered one of the target molecule groups that modulate inflammatory responses. PMID:27041824

  5. The Role of Protein Arginine Methyltransferases in Inflammatory Responses.

    PubMed

    Kim, Ji Hye; Yoo, Byong Chul; Yang, Woo Seok; Kim, Eunji; Hong, Sungyoul; Cho, Jae Youl

    2016-01-01

    Protein arginine methyltransferases (PRMTs) mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I-IV). Although most PRMTs do not require posttranslational modification (PTM) to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required. Inflammation is an essential defense reaction of the body to eliminate harmful stimuli, including damaged cells, irritants, or pathogens. However, chronic inflammation can eventually cause several types of diseases, including some cancers, atherosclerosis, rheumatoid arthritis, and periodontitis. Therefore, inflammation responses should be well modulated. In this review, we briefly discuss the role of PRMTs in the control of inflammation. More specifically, we review the roles of four PRMTs (CARM1, PRMT1, PRMT5, and PRMT6) in modulating inflammation responses, particularly in terms of modulating the transcriptional factors or cofactors related to inflammation. Based on the regulatory roles known so far, we propose that PRMTs should be considered one of the target molecule groups that modulate inflammatory responses. PMID:27041824

  6. Regulation of inflammatory responses by IL-17F

    PubMed Central

    Yang, Xuexian O.; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S.; Broaddus, Russell R.; Zhu, Zhou; Dong, Chen

    2008-01-01

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  7. Regulation of inflammatory responses by IL-17F.

    PubMed

    Yang, Xuexian O; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S; Broaddus, Russell R; Zhu, Zhou; Dong, Chen

    2008-05-12

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor-associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F-deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  8. Morphological features of the inflammatory response in molluscs.

    PubMed

    De Vico, G; Carella, F

    2012-12-01

    Over the last few years, there has been a large increase in studying the biology and pathology of molluscs, predominantly in addressing the molecular patterns involved in their immune-mediated and inflammatory responses. Conversely, the literature-based diagnostic criteria concerning the morphology of the above phenomena still involves pathogenetic confusion and conflicting terminology. A comparison of bibliographic resources, such as the Abridged Glossary of Terms Used in Invertebrate Pathology and the National Status manual for molluscan histopathological examination and analysis from the NOAA, have revealed variability in the definitions of superimposable lesions, emphasising the need for further efforts in establishing standard terminology and methodologies in this field of study. This review suggests some possible solutions for overcoming the use of parallel terminologies in diagnosing inflammation in molluscs and also highlights conflicting features requiring further discussion. PMID:22513124

  9. Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response.

    PubMed

    Vishwakarma, Ajaykumar; Bhise, Nupura S; Evangelista, Marta B; Rouwkema, Jeroen; Dokmeci, Mehmet R; Ghaemmaghami, Amir M; Vrana, Nihal Engin; Khademhosseini, Ali

    2016-06-01

    Current state-of-the-art biomedical implants and tissue engineering methods promise technologies to improve or even restore the function of diseased organs. However, one of the biggest challenges to clinical success is the lack of functional integration. A series of cellular and molecular events following biomaterial implantation poses an important bottleneck for developing breakthrough solutions. With inflammation increasingly recognized as a crucial component influencing regeneration, immunomodulation or immuno-engineering has emerged as a potential solution to overcome this key challenge in regenerative medicine. We postulate possibilities to utilize biomaterial physicochemical modifications to modulate the host inflammatory response and develop strategies for effective biomaterial integration. Biomaterial-based immunomodulation strategies can significantly ameliorate the outcomes of medical implants and tissue engineering therapies. PMID:27138899

  10. Particulate oil shale inhalation and pulmonary inflammatory response in rats

    SciTech Connect

    Wilson, J.S.; Holland, L.M.; Halleck, M.S.; Martinez, E.; Saunders, G.

    1983-01-01

    This experiment detrimetal that long-term inhalation of shale dusts by rats elicits a limited inflammatory response in the lung less profound than that observed in animals exposed to equivalent levels of quartz alone. This observation suggests that organic and inorganic constituents of shale may provide a protective effect. The implications for fibrogenic disease are two-fold: (1) inhalation of oil shale dusts appeared to be less detriemtal than the inhalation of quartz along, and (2) there was no apparent synergistic action of quartz and the complex of organic materials present in shale. Animals exposed to shale dusts failed to develop any significant lung lesions, while all of the animals exposed to quartz developed granulomas and some frank fibrosis.

  11. Titanium dioxide nanoparticles increase inflammatory responses in vascular endothelial cells

    PubMed Central

    Han, Sung Gu; Newsome, Bradley; Hennig, Bernhard

    2013-01-01

    Atherosclerosis is a chronic inflammatory disease that remains the leading cause of death in the United States. Numerous risk factors for endothelial cell inflammation and the development of atherosclerosis have been identified, including inhalation of ultrafine particles. Recently, engineered nanoparticles (NPs) such as titanium (TiO2) NPs have attracted much attention due to their wide range of applications. However, there are also great concerns surrounding potential adverse health effects in vascular systems. Although TiO2 NPs are known to induce oxidative stress and inflammation, the associated signaling pathways have not been well studied. The focus of this work, therefore, deals with examination of the cellular signaling pathways responsible for TiO2 NP-induced endothelial oxidative stress and inflammation. In this study, primary vascular endothelial cells were treated with TiO2 NPs for 2–16 h at concentrations of 0–50 µg/mL. TiO2 NP exposure increased cellular oxidative stress and DNA binding of NF-κB. Further, phosphorylation of Akt, ERK, JNK and p38 was increased in cells exposed to TiO2 NPs. TiO2 NPs also significantly increased induction of mRNA and protein levels of vascular cell adhesion molecule-1 (VCAM-1) and mRNA levels of monocyte chemoattractant protein-1 (MCP-1). Pretreatment with inhibitors for NF-κB (pyrrolidine dithiocarbamate), oxidative stress (epigallocatechin gallate and apocynin), Akt (LY294002), ERK (PD98059), JNK (SP600125) and p38 (SB203580) significantly attenuated TiO2 NP-induced MCP-1 and VCAM-1 gene expression, as well as activation of NF-κB. These data indicate that TiO2 NPs can induce endothelial inflammatory responses via redox-sensitive cellular signaling pathways. PMID:23380242

  12. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  13. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway.

    PubMed

    Liu, Xiaojie; Mei, Zhigang; Qian, Jingping; Zeng, Yongbao; Wang, Mingzhi

    2013-12-01

    Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen), has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that anti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic anti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be involved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment (intravenous injection) reduced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissue. Pretreatment with puerarin (intravenous injection) attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) activation and nuclear factor kappa B (NF-κB) inhibition. These observations were inhibited by the alpha7 nicotinic acetylcholine receptor (α7nAchR) antagonist α-bungarotoxin (α-BGT). In addition, puerarin pretreatment increased the expression of α7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory response. Our results also indicated that the anti-inflammatory effect of puerarin may partly be mediated through the activation of the cholinergic anti-inflammatory pathway. PMID:25206641

  14. Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.

    PubMed

    Kruidenier, Laurens; Kuiper, Ineke; Van Duijn, Wim; Mieremet-Ooms, Marij A C; van Hogezand, Ruud A; Lamers, Cornelis B H W; Verspaget, Hein W

    2003-09-01

    cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes. PMID:12950013

  15. Modulation of inflammatory response of wounds by antimicrobial photodynamic therapy

    PubMed Central

    Sharma, Mrinalini; Gupta, Pradeep Kumar

    2015-01-01

    Background and aims: Management of infections caused by Pseudomonas aeruginosa is becoming difficult due to the rapid emergence of multi-antibiotic resistant strains. Antimicrobial photodynamic therapy (APDT) has a lot of potential as an alternative approach for inactivation of antibiotic resistant bacteria. In this study we report results of our investigations on the effect of poly-L-lysine conjugate of chlorine p6 (pl-cp6) mediated APDT on the healing of P.aeruginosa infected wounds and the role of Nuclear Factor kappa B (NF-kB) induced inflammatory response in this process. Materials and method: Excisional wounds created in Swiss albino mice were infected with ∼107 colony forming units of P.aeruginosa. Mice with wounds were divided into three groups: 1) Uninfected, 2) Infected, untreated control (no light, no pl-cp6), 3) Infected, APDT. After 24 h of infection (day 1 post wounding), the wounds were subjected to APDT [pl-cp6 applied topically and exposed to red light (660 ± 25 nm) fluence of ∼ 60 J/cm2]. Subsequent to APDT, on day 2 and 5 post wounding (p.w), measurements were made on biochemical parameters of inflammation [toll like receptor-4 (TLR-4), NF-kB, Inteleukin (IL)-[1α, IL-β, and IL-2)] and cell proliferation [(fibroblast growth factor-2 (FGF-2), alkaline phosphatase (ALP)]. Results: In comparison with untreated control, while expression of TLR-4, NF-kB (p105 and p50), and proinflammatory interleukins (IL-1α, IL-1β,IL-2) were reduced in the infected wounds subjected to APDT, the levels of FGF-2 and ALP increased, on day 5 p.w. Conclusion: The measurements made on the inflammatory markers and cell proliferation markers suggest that APDT reduces inflammation caused by P.aeruginosa and promotes cell proliferation in wounds. PMID:26557735

  16. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis

    PubMed Central

    Masterson, Joanne C; McNamee, Eóin N; Fillon, Sophie A; Hosford, Lindsay; Harris, Rachel; Fernando, Shahan D; Jedlicka, Paul; Iwamoto, Ryo; Jacobsen, Elizabeth; Protheroe, Cheryl; Eltzschig, Holger K; Colgan, Sean P; Arita, Makoto; Lee, James J; Furuta, Glenn T

    2015-01-01

    Objective Eosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice. Design Acute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy. Results Eosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration. Conclusions Eosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid

  17. Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue

    PubMed Central

    Hottz, Eugenio D.; Medeiros-de-Moraes, Isabel M.; Vieira-de-Abreu, Adriana; de Assis, Edson F.; Vals-de-Souza, Rogério; Castro-Faria-Neto, Hugo C.; Weyrich, Andrew S.; Zimmerman, Guy A.; Bozza, Fernando A.; Bozza, Patrícia T.

    2014-01-01

    Background Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients/Methods Patients with dengue were investigated for platelet-monocyte aggregate formation and markers of monocyte activation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. Results We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, while the exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Conclusions Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue. PMID:25015827

  18. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

    PubMed

    Hodkinson, Duncan J; Khawaja, Nadine; OʼDaly, Owen; Thacker, Michael A; Zelaya, Fernando O; Wooldridge, Caroline L; Renton, Tara F; Williams, Steven C R; Howard, Matthew A

    2015-07-01

    Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top-down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management. PMID:25851460

  19. A pneumococcal pilus influences virulence and host inflammatory responses.

    PubMed

    Barocchi, M A; Ries, J; Zogaj, X; Hemsley, C; Albiger, B; Kanth, A; Dahlberg, S; Fernebro, J; Moschioni, M; Masignani, V; Hultenby, K; Taddei, A R; Beiter, K; Wartha, F; von Euler, A; Covacci, A; Holden, D W; Normark, S; Rappuoli, R; Henriques-Normark, B

    2006-02-21

    Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality world-wide. The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. This work provides evidence that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, long organelles able to extend beyond the polysaccharide capsule, previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the pneumococcal rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhanced adherence to lung epithelial cells, and provided a competitive advantage upon mixed intranasal challenge of mice. Furthermore, a pilus-expressing rlrA islet-positive clinical isolate was more virulent than a nonpiliated deletion mutant, and it out-competed the mutant in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoked a higher TNF response during systemic infection, compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response. PMID:16481624

  20. Acute Pelvic Inflammatory Disease and Clinical Response to Parenteral Doxycycline

    PubMed Central

    Chow, Anthony W.; Malkasian, Kay L.; Marshall, John R.; Guze, Lucien B.

    1975-01-01

    The bacteriology of acute pelvic inflammatory disease (PID) and clinical response to parenteral doxycycline were evaluated in 30 patients. Only 3 of 21 cul-de-sac cultures from PID patients were sterile, whereas all 8 normal control subjects yielded negative results (P< 0.005). Poor correlation was observed between cervical and cul-de-sac cultures. Neisseria gonorrhoeae, isolated from the cervix in 17 patients (57%), was recovered from the cul-de-sac only once. Streptococcus, Peptococcus, Peptostreptococcus, coliforms, and other organisms normally present in the vagina were the predominant isolates recovered from the cul-de-sac. Parenteral doxycycline resulted in rapid resolution of signs and symptoms (within 48 h) in 20 of 27 evaluable patients (74%). In five others, signs and symptoms of infection abated within 4 days. The remaining two patients failed to respond; in both cases, adnexal masses developed during doxycycline therapy. Gonococci were eradicated from the cervix in all but one patient who, nevertheless, had a rapid defervescence of symptoms. There was no clear-cut correlation between the clinical response and in vitro susceptibility of cul-de-sac isolates to doxycycline. These data confirm the usefulness of broad-spectrum antibiotics in acute PID. Culdocentesis is a reliable means of obtaining material for the bacteriological diagnosis of acute PID; however, the pathogenetic role and relative importance of gonococci and various other bacteria in acute PID need to be clarified further. PMID:1169908

  1. Histone deacetylase 5 regulates the inflammatory response of macrophages

    PubMed Central

    Poralla, Lukas; Stroh, Thorsten; Erben, Ulrike; Sittig, Marie; Liebig, Sven; Siegmund, Britta; Glauben, Rainer

    2015-01-01

    Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over-expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-γ treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor α and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-κB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages. PMID:26059794

  2. A pneumococcal pilus influences virulence and host inflammatory responses

    PubMed Central

    Barocchi, M. A.; Ries, J.; Zogaj, X.; Hemsley, C.; Albiger, B.; Kanth, A.; Dahlberg, S.; Fernebro, J.; Moschioni, M.; Masignani, V.; Hultenby, K.; Taddei, A. R.; Beiter, K.; Wartha, F.; von Euler, A.; Covacci, A.; Holden, D. W.; Normark, S.; Rappuoli, R.; Henriques-Normark, B.

    2006-01-01

    Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality world-wide. The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. This work provides evidence that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, long organelles able to extend beyond the polysaccharide capsule, previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the pneumococcal rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhanced adherence to lung epithelial cells, and provided a competitive advantage upon mixed intranasal challenge of mice. Furthermore, a pilus-expressing rlrA islet-positive clinical isolate was more virulent than a nonpiliated deletion mutant, and it out-competed the mutant in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoked a higher TNF response during systemic infection, compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response. PMID:16481624

  3. Apoptosis of resident and inflammatory macrophages before and during the inflammatory response of the virgin bovine mammary gland

    PubMed Central

    2010-01-01

    Background Macrophages may play a prominent role in defense of the bovine mammary gland, and their functionality is necessary for successful eradication of bacterial pathogens. In contrast to necrosis, however, apoptosis has not yet been studied in macrophages from bovine mammary glands. Therefore, the aim of this study was to confirm the occurrence of apoptosis in macrophages from resting heifer mammary glands and during the inflammatory response. Methods Inflammatory response was induced by phosphate buffered saline (PBS) and by lipopolysaccharide (LPS). Resident macrophages (RESMAC) were obtained before and inflammatory macrophages (INFMAC) 24, 48, 72 and 168 hours after inducing inflammatory response in mammary glands of unbred heifers. Cell samples were analyzed for differential counts, apoptosis and necrosis using flow cytometry. Results Populations of RESMAC and INFMAC contained monocyte-like cells and vacuolized cells. Apoptosis was detected differentially in both morphologically different types of RESMAC and INFMAC and also during initiation and resolution of the inflammatory response. In the RESMAC population, approximately one-tenth of monocyte-like cells and one-third of vacuolized cells were apoptotic. In the INFMAC population obtained 24 h after PBS treatment, approximately one-tenth of monocyte-like cells and almost one-quarter of vacuolized cells were apoptotic. At the same time following LPS, however, we observed a significantly lower percentage of apoptotic cells in the population of monocyte-like INFMAC and vacuolized INFMAC. Moreover, a higher percentage of apoptotic cells in INFMAC was detected during all time points after PBS in contrast to LPS. Comparing RESMAC and INFMAC, we observed that vacuolized cells from populations of RESMAC and INFMAC underwent apoptosis more intensively than did monocyte-like cells. Conclusions We conclude that apoptosis of virgin mammary gland macrophages is involved in regulating their lifespan, and it is involved

  4. DISREGULATION OF INFLAMMATORY RESPONSES BY CHRONIC CIRCADIAN DISRUPTION

    PubMed Central

    Castanon-Cervantes, Oscar; Wu, Mingwei; Ehlen, J. Christopher; Paul, Ketema; Gamble, Karen L.; Johnson, Russell L.; Besing, Rachel C.; Menaker, Michael; Gewirtz, Andrew T.; Davidson, Alec J.

    2010-01-01

    Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. Here we show that experimentally-induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified leading to hypothermia and death after 4 consecutive weekly 6h phase-advances of the light-dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of pro-inflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related disregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work. PMID:20944004

  5. Pulpal inflammatory responses following non-carious class V restorations.

    PubMed

    About, I; Murray, P E; Franquin, J C; Remusat, M; Smith, A J

    2001-01-01

    The effects of inflammatory activity following surgical intervention can injure pulp tissues; in severe cases it can lead to pulpal complications. With this article, the authors report on the effects of cavity preparation and restoration events and how they can interact together to reduce or increase the severity of pulpal inflammatory activity in 202 restored Class V cavities. Although some inflammatory activity was observed in the absence of bacteria, the severity of pulpal inflammatory activity was increased when cavity restorations became infected. Zinc oxide eugenol and resin-modified glass ionomer cement prevented bacterial microleakage in cavity restorations, with no severe inflammatory activity observed with these materials. Bacteria were observed in cavities restored with enamel bonding resin and adhesive bonded composites and were associated with severe grades of inflammatory activity. The cavity remaining dentin thickness influenced the grade of inflammatory activity. In the absence of infection, the grade of inflammatory activity decreased after 20 weeks post-operatively. In the presence of infection, the grade of pulpal inflammation remained stable until a minimum of 30 weeks had elapsed. PMID:11504432

  6. Triggering of inflammatory response by myeloperoxidase-oxidized LDL.

    PubMed

    Boudjeltia, Karim Zouaoui; Legssyer, Ilham; Van Antwerpen, Pierre; Kisoka, Roger Lema; Babar, Sajida; Moguilevsky, Nicole; Delree, Paul; Ducobu, Jean; Remacle, Claude; Vanhaeverbeek, Michel; Brohee, Dany

    2006-10-01

    The oxidation theory proposes that LDL oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis in triggering inflammation. In contrast to the copper-modified LDL, there are few studies using myeloperoxidase-modified LDL (Mox-LDL) as an inflammation inducer. Our aim is to test whether Mox-LDL could constitute a specific inducer of the inflammatory response. Albumin, which is the most abundant protein in plasma and which is present to an identical concentration of LDL in the intima, was used for comparison. The secretion of IL-8 by endothelial cells (Ea.hy926) and TNF-alpha by monocytes (THP-1) was measured in the cell medium after exposure of these cells to native LDL, native albumin, Mox-LDL, or Mox-albumin. We observed that Mox-LDL induced a 1.5- and 2-fold increase (ANOVA; P < 0.001) in IL-8 production at 100 microg/mL and 200 microg/mL, respectively. The incubation of THP-1 cells with Mox-LDL (100 microg/mL) increased the production of TNF-alpha 2-fold over the control. Native LDL, albumin, and Mox-albumin showed no effect in either cellular types. The myeloperoxidase-modified LDL increase in cytokine release by endothelial and monocyte cells and by firing both local and systemic inflammation could induce atherogenesis and its development. PMID:17167545

  7. Acute inflammatory response in spinal cord following impact injury.

    PubMed

    Carlson, S L; Parrish, M E; Springer, J E; Doty, K; Dossett, L

    1998-05-01

    Numerous factors are involved in the spread of secondary damage in spinal cord after traumatic injury, including ischemia, edema, increased excitatory amino acids, and oxidative damage to the tissue from reactive oxygen species. Neutrophils and macrophages can produce reactive oxygen species when activated and thus may contribute to the lipid peroxidation that is known to occur after spinal cord injury. This study examined the rostral-caudal distribution of neutrophils and macrophages/microglia at 4, 6, 24, and 48 h after contusion injury to the T10 spinal cord of rat (10 g weight, 50 mm drop). Neutrophils were located predominantly in necrotic regions, with a time course that peaked at 24 h as measured with assays of myeloperoxidase activity (MPO). The sharpest peak of MPO activity was localized between 4 mm rostral and caudal to the injury. Macrophages/microglia were visualized with antibodies against ED1 and OX-42. Numerous cells with a phagocytic morphology were present by 24 h, with a higher number by 48 h. These cells were predominantly located within the gray matter and dorsal funiculus white matter. The number of cells gradually declined through 6 mm rostral and caudal to the lesion. OX-42 staining also revealed reactive microglia with blunt processes, particularly at levels distant to the lesion. The number of macrophages/microglia was significantly correlated with the amount of tissue damage at each level. Treatments to decrease the inflammatory response are likely to be beneficial to recovery of function after traumatic spinal cord injury. PMID:9582256

  8. Role of Fiber Length on Phagocytosis & Inflammatory Response

    NASA Astrophysics Data System (ADS)

    Turkevich, Leonid; Stark, Carahline; Champion, Julie

    2014-03-01

    Asbestos fibers have long been associated with lung cancer death. The inability of immune cells (e.g. macrophages) to effectively remove asbestos leads to chronic inflammation and disease. This study examines the role of fiber length on toxicity at the cellular level using model glass fibers. A major challenge is obtaining single diameter fibers but differing in length. Samples of 1 micron diameter fibers with different length distributions were prepared: short fibers (less than 15 microns) by aggressive crushing, and long fibers (longer than 15 microns) by successive sedimentation. Time-lapse video microscopy monitored the interaction of MH-S murine alveolar macrophages with the fibers: short fibers were easily internalized by the macrophages, but long fibers resisted internalization over many hours. Production of TNF- α (tumor necrosis factor alpha), a general inflammatory secreted cytokine, and Cox-2 (cyclo-oxygenase-2), an enzyme that produces radicals, each exhibited a dose-dependence that was greater for long than for short fibers. These results corroborate the importance of fiber length in both physical and biochemical cell response and support epidemiological observations of higher toxicity for longer fibers.

  9. Acute hypoxemia in humans enhances the neutrophil inflammatory response.

    PubMed

    Tamura, Douglas Y; Moore, Ernest E; Partrick, David A; Johnson, Jeffrey L; Offner, Patrick J; Silliman, Christopher C

    2002-04-01

    The neutrophil (PMN) is regarded as a key component in the hyperinflammatory response known as the systemic inflammatory response syndrome. Acute respiratory distress syndrome (ARDS) and subsequent multiple organ failure (MOF) are related to the severity of this hyperinflammation. ICU patients who are at highest risk of developing MOF may have acute hypoxic events that complicate their hospital course. This study was undertaken to evaluate the effects of acute hypoxia and subsequent hypoxemia on circulating PMNs in human volunteers. Healthy subjects were exposed to a changing O2/N2 mixture until their O2 saturation (SaO2) reached a level of 68% saturation. These subjects were then exposed to room air and then returned to their baseline SaO2. PMNs were isolated from pre- and post-hypoxemic arterial blood samples and were then either stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or PMA alone, or they were primed with L-alpha-phosphatidylcholine, beta-acetyl-gamma-O-alkyl (PAF) followed by fMLP activation. Reactive oxygen species generation as measured by superoxide anion production was enhanced in primed PMNs after hypoxemia. Protease degranulation as measured by elastase release was enhanced in both quiescent PMNs and primed PMNs after fMLP activation following the hypoxemic event. Adhesion molecule upregulation as measured by CD11b/CD18, however, was not significantly changed after hypoxemia. Apoptosis of quiescent PMNs was delayed after the hypoxemic event. TNFalpha, IL-1, IL-6, and IL-8 cytokine levels were unchanged following hypoxemia. These results indicate that relevant acute hypoxemic events observed in the clinical setting enhance several PMN cytotoxic functions and suggest that a transient hypoxemic insult may promote hyperinflammation. PMID:11954825

  10. Helicobacter hepaticus Induces an Inflammatory Response in Primary Human Hepatocytes

    PubMed Central

    Kleine, Moritz; Worbs, Tim; Schrem, Harald; Vondran, Florian W. R.; Kaltenborn, Alexander; Klempnauer, Jürgen; Förster, Reinhold; Josenhans, Christine; Suerbaum, Sebastian; Bektas, Hüseyin

    2014-01-01

    Helicobacter spp. on human liver cells, resulting in an inflammatory response with increased synthesis of inflammatory mediators and consecutive monocyte activation. PMID:24932686

  11. Burn size determines the inflammatory and hypermetabolic response

    PubMed Central

    Jeschke, Marc G; Mlcak, Ronald P; Finnerty, Celeste C; Norbury, William B; Gauglitz, Gerd G; Kulp, Gabriela A; Herndon, David N

    2007-01-01

    Background Increased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function. Methods Pediatric burned patients were divided into four burn size groups: <40% total body surface area (TBSA) burn, 40–59% TBSA burn, 60–79% TBSA burn, and >80% TBSA burn. Demographic and clinical data, hypermetabolism, the inflammatory response, body composition, the muscle protein net balance, serum and urine hormones and proteins, and cardiac function and changes in liver size were determined. Results One hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (<40% TBSA burn, n = 43; 40–59% TBSA burn, n = 79; 60–79% TBSA burn, n = 46; >80% TBSA burn, n = 21). Patients with larger burns had more operations, a greater incidence of infections and sepsis, and higher mortality rates compared with the other groups (P < 0.05). The percentage predicted resting energy expenditure was highest in the >80% TBSA group, followed by the 60–79% TBSA burn group (P < 0.05). Children with >80% burns lost the most body weight, lean body mass, muscle protein and bone mineral content (P < 0.05). The urine cortisol concentration was highest in the 80–99% and 60–79% TBSA burn groups, associated with significant myocardial depression and increased change in liver size (P < 0.05). The cytokine profile showed distinct differences in expression of IL-8, TNF, IL-6, IL-12p70, monocyte chemoattractant protein-1 and granulocyte–macrophage colony-stimulating factor (P < 0.05). Conclusion Morbidity and mortality in burned patients is burn size dependent, starts at a 60% TBSA burn and is due to an

  12. ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-κB signaling activity

    SciTech Connect

    Liu, Xin-Hua; Bauman, William A.; Cardozo, Christopher

    2015-08-14

    Transcription factors of the nuclear factor-kappa B (NF-κB) family play a pivotal role in inflammation, immunity and cell survival responses. Recent studies revealed that NF-κB also regulates the processes of muscle atrophy. NF-κB activity is regulated by various factors, including ankyrin repeat domain 2 (AnkrD2), which belongs to the muscle ankyrin repeat protein family. Another member of this family, AnkrD1 is also a transcriptional effector. The expression levels of AnkrD1 are highly upregulated in denervated skeletal muscle, suggesting an involvement of AnkrD1 in NF-κB mediated cellular responses to paralysis. However, the molecular mechanism underlying the interactive role of AnkrD1 in NF-κB mediated cellular responses is not well understood. In the current study, we examined the effect of AnkrD1 on NF-κB activity and determined the interactions between AnkrD1 expression and NF-κB signaling induced by TNFα in differentiating C2C12 myoblasts. TNFα upregulated AnkrD1 mRNA and protein levels. AnkrD1-siRNA significantly increased TNFα-induced transcriptional activation of NF-κB, whereas overexpression of AnkrD1 inhibited TNFα-induced NF-κB activity. Co-immunoprecipitation studies demonstrated that AnkrD1 was able to bind p50 subunit of NF-κB and vice versa. Finally, CHIP assays revealed that AnkrD1 bound chromatin at a NF-κB binding site in the AnrkD2 promoter and required NF-κB to do so. These results provide evidence of signaling integration between AnkrD1 and NF-κB pathways, and suggest a novel anti-inflammatory role of AnkrD1 through feedback inhibition of NF-κB transcriptional activity by which AnkrD1 modulates the balance between physiological and pathological inflammatory responses in skeletal muscle. - Highlights: • AnkrD1 is upregulated by TNFα and represses NF-κB-induced transcriptional activity. • AnkrD1 binds to p50 subunit of NF-κB and is recruited to NF-κB bound to chromatin. • AnkrD1 mediates a feed-back inhibitory loop

  13. Prokineticin 1 Induces Inflammatory Response in Human Myometrium

    PubMed Central

    Gorowiec, Marta R.; Catalano, Rob D.; Norman, Jane E.; Denison, Fiona C.; Jabbour, Henry N.

    2011-01-01

    The infiltration of human myometrium and cervix with leukocytes and the formation of a pro-inflammatory environment within the uterus have been associated with the initiation of both term and preterm parturition. The mechanism regulating the onset of this pro-inflammatory cascade is not fully elucidated. We demonstrate that prokineticin 1 (PROK1) is up-regulated in human myometrium and placenta during labor. The expression of PROK1 receptor remains unchanged during labor and is abundantly expressed in the myometrium. Gene array analysis identified 65 genes up-regulated by PROK1 in human myometrium, mainly cytokines and chemokines, including IL-1β, chemokine C-C motif ligand 3, and colony-stimulating factor 3. In addition, we demonstrate that PROK1 increases the expression of chemokine C-C motif ligand 20, IL-6, IL-8, prostaglandin synthase 2, and prostaglandin E2 and F2α secretion. The treatment of myometrial explants with 100 ng/mL of lipopolysaccharide up-regulates the expression of PROK1, PROK1 receptor, and inflammatory mediators. The infection of myometrial explants with lentiviral microRNA targeting PROK1, preceding treatment with lipopolysaccharide, reduces the expression of inflammatory genes. We propose that PROK1 is a novel inflammatory mediator that can contribute to the onset of human parturition at term and partially mediate premature onset of inflammatory pathways during bacterial infection. PMID:21983634

  14. Early inflammatory response in epithelial ovarian tumor cyst fluids.

    PubMed

    Kristjánsdóttir, Björg; Partheen, Karolina; Fung, Eric T; Yip, Christine; Levan, Kristina; Sundfeldt, Karin

    2014-10-01

    Mortality rates for epithelial ovarian cancer (EOC) are high, mainly due to late-stage diagnosis. The identification of biomarkers for this cancer could contribute to earlier diagnosis and increased survival rates. Given that chronic inflammation plays a central role in cancer initiation and progression, we selected and tested 15 cancer-related cytokines and growth factors in 38 ovarian cyst fluid samples. We used ovarian cyst fluid since it is found in proximity to the pathology and mined it for inflammatory biomarkers suitable for early detection of EOC. Immunoprecipitation and high-throughput sample fractionation were obtained by using tandem antibody libraries bead and mass spectrometry. Two proteins, monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleucin-8 (IL-8/CXCL8), were significantly (P < 0.0001) higher in the malignant (n = 16) versus benign (n = 22) tumor cysts. Validation of MCP-1, IL-8, and growth-regulated protein-α (GROα/CXCL1) was performed with ELISA in benign, borderline, and malignant cyst fluids (n = 256) and corresponding serum (n = 256). CA125 was measured in serum from all patients and used in the algorithms performed. MCP-1, IL-8, and GROα are proinflammatory cytokines and promoters of tumor growth. From 5- to 100-fold higher concentrations of MCP-1, IL-8 and GROα were detected in the cyst fluids compared to the serum. Significant (P < 0.001) cytokine response was already established in borderline cyst fluids and stage I EOC. In serum a significant (P < 0.01) increase of IL-8 and GROα was found, but not until stage I and stage III EOC, respectively. These findings confirm that early events in tumorigenesis can be analyzed and detected in the tumor environment and we conclude that ovarian cyst fluid is a promising source in the search for new biomarkers for early ovarian tumors. PMID:24947406

  15. Lactic acid delays the inflammatory response of human monocytes

    SciTech Connect

    Peter, Katrin; Rehli, Michael; Singer, Katrin; Renner-Sattler, Kathrin; Kreutz, Marina

    2015-02-13

    Lactic acid (LA) accumulates under inflammatory conditions, e.g. in wounds or tumors, and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and TNF secretion of human LPS-stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from lactate- or pH-effects, monocytes were treated for one or four hours with LPS in the presence of physiological concentrations of LA, sodium lactate (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most LPS-induced genes was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. TNF and IL-23) or chemokines (e.g. CCL2 and CCL7). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of LPS-signaling pathways revealed that LA delayed the phosphorylation of protein kinase B (AKT) as well as the degradation of IκBα. Consistently, the LPS-induced nuclear accumulation of NFκB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of human monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the tumor environment. - Highlights: • Lactic acid broadly delays LPS-induced gene expression in human monocytes. • Expression of important monocyte effector molecules is affected by lactic acid. • Interference of lactic acid with TLR signaling causes the delayed gene expression. • The profound effect of lactic acid might contribute to immune suppression in tumors.

  16. ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-κB signaling activity.

    PubMed

    Liu, Xin-Hua; Bauman, William A; Cardozo, Christopher

    2015-08-14

    Transcription factors of the nuclear factor-kappa B (NF-κB) family play a pivotal role in inflammation, immunity and cell survival responses. Recent studies revealed that NF-κB also regulates the processes of muscle atrophy. NF-κB activity is regulated by various factors, including ankyrin repeat domain 2 (AnkrD2), which belongs to the muscle ankyrin repeat protein family. Another member of this family, AnkrD1 is also a transcriptional effector. The expression levels of AnkrD1 are highly upregulated in denervated skeletal muscle, suggesting an involvement of AnkrD1 in NF-κB mediated cellular responses to paralysis. However, the molecular mechanism underlying the interactive role of AnkrD1 in NF-κB mediated cellular responses is not well understood. In the current study, we examined the effect of AnkrD1 on NF-κB activity and determined the interactions between AnkrD1 expression and NF-κB signaling induced by TNFα in differentiating C2C12 myoblasts. TNFα upregulated AnkrD1 mRNA and protein levels. AnkrD1-siRNA significantly increased TNFα-induced transcriptional activation of NF-κB, whereas overexpression of AnkrD1 inhibited TNFα-induced NF-κB activity. Co-immunoprecipitation studies demonstrated that AnkrD1 was able to bind p50 subunit of NF-κB and vice versa. Finally, CHIP assays revealed that AnkrD1 bound chromatin at a NF-κB binding site in the AnrkD2 promoter and required NF-κB to do so. These results provide evidence of signaling integration between AnkrD1 and NF-κB pathways, and suggest a novel anti-inflammatory role of AnkrD1 through feedback inhibition of NF-κB transcriptional activity by which AnkrD1 modulates the balance between physiological and pathological inflammatory responses in skeletal muscle. PMID:26102030

  17. The "bioregulatory effect of exercise" on the innate/inflammatory responses.

    PubMed

    Ortega, Eduardo

    2016-06-01

    The effects of exercise on the innate response are primarily mediated by the SNS (sympathetic nervous system) and/or the HPA (hypothalamic-pituitary-adrenal) axis and by stress proteins such as Hsp72. Regular exercise can induce immuno-neuroendocrine stabilization in persons with deregulated inflammatory and stress feedback by reducing the presence of stress hormones and inflammatory cytokines. Anti-inflammatory and "anti-stress" responses seem also to be induced (paradoxically, opposite to the effects in healthy persons) after sessions of exercise, being a promising strategy for treating certain inflammatory pathologies. Nevertheless, the biomedical side effects of exercise are also needed to be considered. This article defines the "Bioregulatory Effect of Exercise" to be one that reduces or prevents any excessive effect of inflammatory mediators and stimulates (or at least does not impair) the innate defences (i.e. chemotaxis, phagocytosis, and microbicidal activities) against pathogens. It also generates immunophysiological adaptations through an optimal balance between the pro- and the anti-inflammatory responses. These effects are mediated via immuno-neuroendocrine interactions. This review analyses concepts and conclusions related to how exercise affects the innate and/or inflammatory responses and discusses some paradoxical interpretations relevant for the practical use of exercise in treating infectious and inflammatory diseases. A potential role of exercise as hormesis strategy and the concept of exercise immunization are also discussed. PMID:26979741

  18. A novel pathway by which the environmental toxin 4-Nonylphenol may promote an inflammatory response in inflammatory bowel disease

    PubMed Central

    Kim, Albert; Jung, Byeong Ho; Cadet, Patrick

    2014-01-01

    Background 4-Nonylphenol is a ubiquitous environmental toxin that is formed as a byproduct in the manufacturing and/or sewage treatment of regular household items. Previous work in our lab has implicated 4-NP in the progression of autoimmune diseases such as inflammatory bowel disease in which macrophages mistakenly attack the intestinal linings, causing chronic inflammation. Several key pro-and anti-inflammatory molecules have been shown to be involved in the manifestation of this disease, including IL-23A, COX-2, IL-8, TLR-4, and IL-10. Material/Methods 4-NP’s effects on these known mediators of IBD were effectively analyzed using a novel model for IBD, by which 4-NP may promote an inflammatory response. Data were collected using DNA Microarray, RT-PCR, and ELISA, after 48 hour treatment of U937 histiocytic lymphocyte cells and COLO320DM human intestinal epithelial cells with 1 nM and 5 nM concentrations of 4-NP. Results Significant dysregulation of the expression of both pro- and anti-inflammatory genes was observed in U937 cells that would promote and prolong inflammation. However, TLR-4, IL-8, and COX-2 gene expressions showed unprecedented effects in COLO320DM cells suggesting that these genes mediate apoptotic processes within the gastrointestinal tract. Conclusions Overall, our results suggest that 4-NP administration engenders immune responses linked to apoptotic processes via dysregulation of macrophage signaling. In sum, 4-NP appears to increases the risk of developing inflammatory bowel disease by promoting or prolonging adverse progression of inflammation in the gastrointestinal tract. PMID:24717721

  19. Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome

    PubMed Central

    Arkader, R; Troster, E J; Lopes, M R; Júnior, R R; Carcillo, J A; Leone, C; Okay, T S

    2006-01-01

    Aims To evaluate whether procalcitonin (PCT) and C reactive protein (CRP) are able to discriminate between sepsis and systemic inflammatory response syndrome (SIRS) in critically ill children. Methods Prospective, observational study in a paediatric intensive care unit. Kinetics of PCT and CRP were studied in patients undergoing open heart surgery with cardiopulmonary bypass (CPB) (SIRS model; group I1) and patients with confirmed bacterial sepsis (group II). Results In group I, PCT median concentration was 0.24 ng/ml (reference value <2.0 ng/ml). There was an increment of PCT concentrations which peaked immediately after CPB (median 0.58 ng/ml), then decreased to 0.47 ng/ml at 24 h; 0.33 ng/ml at 48 h, and 0.22 ng/ml at 72 h. CRP median concentrations remained high on POD1 (36.6 mg/l) and POD2 (13.0 mg/l). In group II, PCT concentrations were high at admission (median 9.15 ng/ml) and subsequently decreased in 11/14 patients who progressed favourably (median 0.31 ng/ml). CRP levels were high in only 11/14 patients at admission. CRP remained high in 13/14 patients at 24 h; in 12/14 at 48 h; and in 10/14 patients at 72 h. Median values were 95.0, 50.9, 86.0, and 20.3 mg/l, respectively. The area under the ROC curve was 0.99 for PCT and 0.54 for CRP. Cut off concentrations to differentiate SIRS from sepsis were >2 ng/ml for PCT and >79 mg/l for CRP. Conclusion PCT is able to differentiate between SIRS and sepsis while CRP is not. Moreover, unlike CRP, PCT concentrations varied with the evolution of sepsis. PMID:16326799

  20. Co-Regulation of NF-κB and Inflammasome-Mediated Inflammatory Responses by Myxoma Virus Pyrin Domain-Containing Protein M013

    PubMed Central

    Rahman, Masmudur M.; Mohamed, Mohamed R.; Kim, Manbok; Smallwood, Sherin; McFadden, Grant

    2009-01-01

    NF-κB and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The viral M013 protein was previously shown to bind host ASC-1 protein and inhibit the cellular inflammasome complex that regulates the activation and secretion of caspase 1-regulated cytokines such as IL-1β and IL-18. Here, we report that human THP-1 monocytic cells infected with a MYXV construct deleted for the M013L gene (vMyxM013-KO), in stark contrast to the parental MYXV, rapidly induce high levels of secreted pro-inflammatory cytokines like TNF, IL-6, and MCP-1, all of which are regulated by NF-κB. The induction of these NF-κB regulated cytokines following infection with vMyxM013-KO was also confirmed in vivo using THP-1 derived xenografts in NOD-SCID mice. vMyxM013-KO virus infection specifically induced the rapid phosphorylation of IKK and degradation of IκBα, which was followed by nuclear translocation of NF-κB/p65. Even in the absence of virus infection, transiently expressed M013 protein alone inhibited cellular NF-κB-mediated reporter gene expression and nuclear translocation of NF-κB/p65. Using protein/protein interaction analysis, we show that M013 protein also binds directly with cellular NF-κB1, suggesting a direct physical and functional linkage between NF-κB1 and ASC-1. We further demonstrate that inhibition of the inflammasome with a caspase-1 inhibitor did not prevent the induction of NF-κB regulated cytokines following infection with vMyxM013-KO virus, but did block the activation of IL-1β. Thus, the poxviral M013 inhibitor exerts a dual immuno-subversive role in the simultaneous co-regulation of both the cellular inflammasome complex and NF-κB-mediated pro-inflammatory responses. PMID:19851467

  1. Effect of Kramecyne on the Inflammatory Response in Lipopolysaccharide-Stimulated Peritoneal Macrophages

    PubMed Central

    Sánchez-Miranda, E.; Lemus-Bautista, J.; Pérez, S.; Pérez-Ramos, J.

    2013-01-01

    Kramecyne is a new peroxide, it was isolated from Krameria cytisoides, methanol extract, and this plant was mostly found in North and South America. This compound showed potent anti-inflammatory activity; however, the mechanisms by which this compound exerts its anti-inflammatory effect are not well understood. In this study, we examined the effects of kramecyne on inflammatory responses in mouse lipopolysaccharide- (LPS-) induced peritoneal macrophages. Our findings indicate that kramecyne inhibits LPS-induced production of tumor necrosis factor (TNF-α) and interleukin- (IL-) 6. During the inflammatory process, levels of cyclooxygenase- (COX-) 2, nitric oxide synthase (iNOS), and nitric oxide (NO) increased in mouse peritoneal macrophages; however, kramecyne suppressed them significantly. These results provide novel insights into the anti-inflammatory actions and support its potential use in the treatment of inflammatory diseases. PMID:23573152

  2. Foxo1-mediated inflammatory response after cerebral hemorrhage in rats.

    PubMed

    Li, Zhenyu; He, Qi; Zhai, Xuan; You, Yan; Li, Lingyu; Hou, Yanghao; He, Faming; Zhao, Yong; Zhao, Jing

    2016-08-26

    The forkhead box O (Foxo) family of transcription factors plays a crucial role in cell apoptosis, immune regulation, and tissue development. Foxo1, as the foremost member of the Foxo family, regulates a wide range of molecular signals in many tissues, including tumor, liver, and brain. This study investigated Foxo1 expression at different time points and in different brain areas, and the role of Foxo1 in vivo in regulating inflammatory injury in a rat model of autologous blood-injected cerebral hemorrhage injury. We found that Foxo1 expression peaked at 12h post-intracerebral hemorrhage (ICH) and in the ipsilateral corpus striatum. Foxo1 knockdown by Foxo1 siRNA decreased ICH injury, improved neurological function, and decreased the expression of inflammatory factors downstream of the Foxo1 pathway, including TLR4, NF-κB, TNF-α, IL-1β, and IL-18. Foxo1 knockdown also decreased the expression and activity of myeloperoxidase, IL-1β, and IL-18. In conclusion, our findings demonstrate that Foxo1 is a key regulator of inflammatory injury in rats after ICH. By identifying the molecular mechanisms of Foxo1/TLR4/NF-κB signaling, we provide a novel rationale for therapeutic approaches to managing inflammatory injury after ICH. PMID:27288017

  3. The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages.

    PubMed

    Kim, Yoon Hee; Kim, Dae Hwan; Lim, Hwan; Baek, Doo-Yeon; Shin, Hyun-Kyung; Kim, Jin-Kyung

    2009-04-01

    Methylsulfonylmethane (MSM), also known as dimethyl sulfone and methyl sulfone, is an organic sulfur-containing compound that occurs naturally in a variety of fruits, vegetables, grains, and animals, including humans. In the present study, we demonstrated the anti-inflammatory effects of MSM in lipopolysaccharide (LPS)-stimulated murine macrophages, RAW264.7 cells. MSM significantly inhibited the release of nitric oxide and prostaglandin E(2) by alleviating the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW264.7 cells. Furthermore, the levels of interleukin-6 and tumor necrosis factor-alpha were decreased by MSM treatment in cell culture supernatants. Further study indicated that the translocation of the p65 subunit of nuclear factor (NF)-kappaB to the nucleus was inhibited by MSM treatment in LPS-stimulated RAW264.7 cells, in which it helped block degradation of inhibitor of NF-kappaB. In addition, in vivo studies demonstrated that topical administration of MSM at 500-1250 microg/ear resulted in similar inhibitory activities in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Collectively, theses results indicate that MSM inhibits LPS-induced release of pro-inflammatory mediators in murine macrophages through downregulation of NF-kappaB signaling. PMID:19336900

  4. Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

    EPA Science Inventory

    Background Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immunoinflammatory function and genomic signaling in those with heightened inflammatory responsive...

  5. Endothelial Inflammatory Transcriptional Responses to an Altered Plasma Exposome Following Inhalation of Diesel Emissions

    EPA Science Inventory

    BACKGROUND:Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology.OBJECTIVES:Previously, we found that canonical inflammatory response tra...

  6. ANTIOXIDANT SUPPLEMENTATION AND NASAL INFLAMMATORY RESPONSES AMONG YOUNG ASTHMATICS EXPOSED TO HIGH LEVELS OF OZONE

    EPA Science Inventory

    Background: Recent studies examining the inflammatory response in atopic asthma to ozone suggest a release of soluble mediators of inflammation factors that might be related to reactive oxygen species (ROS). Antioxidant could prove useful in subjects exposed to additional oxidati...

  7. cAMP Response Element-binding Protein (CREB) and Nuclear Factor κB Mediate the Tamoxifen-induced Up-regulation of Glutamate Transporter 1 (GLT-1) in Rat Astrocytes*

    PubMed Central

    Karki, Pratap; Webb, Anton; Smith, Keisha; Lee, Kyuwon; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2013-01-01

    Tamoxifen (TX), a selective estrogen receptor modulator, exerts antagonistic effects on breast tissue and is used to treat breast cancer. Recent evidence also suggests that it may act as an agonist in brain tissue. We reported previously that TX enhanced the expression and function of glutamate transporter 1 (GLT-1) in rat astrocytes, an effect that was mediated by TGF-α. To gain further insight into the mechanisms that mediate TX-induced up-regulation of GLT-1 (EAAT2 in humans), we investigated its effect on GLT-1 at the transcriptional level. TX phosphorylated the cAMP response element-binding protein (CREB) and recruited CREB to the GLT-1 promoter consensus site. The effect of TX on astrocytic GLT-1 was attenuated by the inhibition of PKA, the upstream activator of the CREB pathway. In addition, the effect of TX on GLT-1 promoter activity was abolished by the inhibition of the NF-κB pathway. Furthermore, TX recruited the NF-κB subunits p65 and p50 to the NF-κB binding domain of the GLT-1 promoter. Mutation of NF-κB (triple, −583/-282/-251) or CRE (-308) sites on the GLT-1 promoter led to significant repression of the promoter activity, but neither mutant completely abolished the TX-induced GLT-1 promoter activity. Mutation of both the NF-κB (-583/-282/-251) and CRE (-308) sites led to a complete abrogation of the effect of TX on GLT-1 promoter activity. Taken together, our findings establish that TX regulates GLT-1 via the CREB and NF-κB pathways. PMID:23955341

  8. Cells from Degenerative Intervertebral Discs Demonstrate Unfavorable Responses to Mechanical and Inflammatory Stimuli: A Pilot Study

    PubMed Central

    Sowa, Gwendolyn A.; Coelho, J. Paulo; Vo, Nam V.; Pacek, Corey; Westrick, Edward; Kang, James D.

    2016-01-01

    Objective Mechanical forces and inflammatory signaling influence intervertebral disc matrix homeostasis. We hypothesized that annulus fibrosus cells from degenerative discs would have altered responses to mechanical and inflammatory stimuli compared with cells isolated from normal discs. Design Annulus fibrosus cells were isolated from New Zealand White rabbits with normal and magnetic resonance imaging-confirmed degenerative discs created by annular stab. Cells were cultured with and without inflammatory and mechanical stimuli (tensile strain). After 4 or 24 hrs, the mRNA expression of inflammatory, catabolic, and anabolic genes was measured by reverse transcription polymerase chain reaction. Results Baseline gene expression differences were noted between cells from normal and degenerative discs. Degenerative cells demonstrated a more proinflammatory response profile to inflammatory and mechanical stimuli and loss of the beneficial effects of mechanical signaling. Decreased expression of catabolic and anabolic genes was observed in degenerative cells under conditions of inflammatory and mechanical stimuli. Conclusions These data demonstrate that degenerative cells have a decreased capacity to respond positively to beneficial levels of mechanical strain and demonstrate an exaggerated response to an inflammatory stimulus. This may, in part, help to explain differential responses to motion-based therapies in patients with intervertebral disc degeneration. PMID:22760106

  9. Sleep deprivation attenuates inflammatory responses and ischemic cell death.

    PubMed

    Weil, Zachary M; Norman, Greg J; Karelina, Kate; Morris, John S; Barker, Jacqueline M; Su, Alan J; Walton, James C; Bohinc, Steven; Nelson, Randy J; DeVries, A Courtney

    2009-07-01

    Although the biological function of sleep remains uncertain, the consequences of sleep deprivation are well-described and are reported to be detrimental to cognitive function and affective well-being. Sleep deprivation also is strongly associated with elevated risk factors for cardiovascular disease. We used a mouse model of cardiac arrest/cardiopulmonary resuscitation to test the hypothesis that acute sleep deprivation would exacerbate neuroinflammation and neurodegeneration after global ischemia. The resulting data led to a rejection of our hypothesis that sleep deprivation is necessarily detrimental. Indeed, acute sleep deprivation (ASD) was associated with a reduction in ischemia-induced interleukin 1beta (IL-1beta) gene expression and attenuation of neuronal damage in the hippocampus. Further, sleep deprivation increased gene expression of two anti-inflammatory cytokines, IL-6 and IL-10 that are associated with improved ischemic outcome. To determine whether the anti-inflammatory properties of ASD were specific to ischemia, mice were treated systemically with lipopolysaccharide (LPS), a potent inflammogen. Acute sleep deprivation attenuated the central and peripheral increase in tumor necrosis factor-alpha (TNFalpha) and increased IL-10 expression. Together, the ischemia and LPS data suggest that, ASD produces an anti-inflammatory bias that could be exploited to improve medical procedures that are compromised by inflammation. PMID:19409382

  10. 5-Aminolevulinic acid regulates the inflammatory response and alloimmune reaction.

    PubMed

    Fujino, Masayuki; Nishio, Yoshiaki; Ito, Hidenori; Tanaka, Tohru; Li, Xiao-Kang

    2016-08-01

    5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid and precursor of heme and protoporphyrin IX (PpIX). Exogenously administrated 5-ALA increases the accumulation of PpIX in tumor cells specifically due to the compromised metabolism of 5-ALA to heme in mitochondria. PpIX emits red fluorescence by the irradiation of blue light and the formation of reactive oxygen species and singlet oxygen. Thus, performing a photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-ALA have given rise to a new strategy for tumor diagnosis and therapy. In addition to the field of tumor therapy, 5-ALA has been implicated in the treatment of inflammatory disease, autoimmune disease and transplantation due to the anti-inflammation and immunoregulation properties that are elicited with the expression of heme oxygenase (HO)-1, an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide (CO), in combination with sodium ferrous citrate (SFC), because an inhibitor of HO-1 abolishes the effects of 5-ALA. Furthermore, NF-E2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and heme are involved in the HO-1 expression. Biliverdin and CO are also known to have anti-apoptotic, anti-inflammatory and immunoregulatory functions. We herein review the current use of 5-ALA in inflammatory diseases, transplantation medicine, and tumor therapy. PMID:26643355

  11. Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base

    PubMed Central

    Landis, R. Clive; Brown, Jeremiah R.; Fitzgerald, David; Likosky, Donald S.; Shore-Lesserson, Linda; Baker, Robert A.; Hammon, John W.

    2014-01-01

    Abstract: A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture “self-identified” anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the “Outcomes 2010” consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a “multiple hit” hypothesis, whereby clinically effective suppression of the systemic inflammatory response

  12. Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base.

    PubMed

    Landis, R Clive; Brown, Jeremiah R; Fitzgerald, David; Likosky, Donald S; Shore-Lesserson, Linda; Baker, Robert A; Hammon, John W

    2014-09-01

    A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture "self-identified" anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the "Outcomes 2010" consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a "multiple hit" hypothesis, whereby clinically effective suppression of the systemic inflammatory response requires hitting multiple

  13. Role of virulence factors on host inflammatory response induced by diarrheagenic Escherichia coli pathotypes.

    PubMed

    Sanchez-Villamil, Javier; Navarro-Garcia, Fernando

    2015-01-01

    Pathogens are able to breach the intestinal barrier, and different bacterial species can display different abilities to colonize hosts and induce inflammation. Inflammatory response studies induced by enteropathogens as Escherichia coli are interesting since it has acquired diverse genetic mobile elements, leading to different E. coli pathotypes. Diarrheagenic E. coli secrete toxins, effectors and virulence factors that exploit the host cell functions to facilitate the bacterial colonization. Many bacterial proteins are delivered to the host cell for subverting the inflammatory response. Hereby, we have highlighted the specific processes used by E. coli pathotypes, by that subvert the inflammatory pathways. These mechanisms include an arrangement of pro- and anti-inflammatory responses to favor the appropriate environmental niche for the bacterial survival and growth. PMID:26059623

  14. Nutrition before and during Surgery and the Inflammatory Response of the Heart: A Randomized Controlled Trial

    PubMed Central

    Visser, Marlieke; Niessen, Hans W. M.; Kok, Wouter E. M.; Cocchieri, Riccardo; Wisselink, Willem; van Leeuwen, Paul A. M.; de Mol, Bas A. J. M.

    2015-01-01

    Major surgery induces a long fasting time and provokes an inflammatory response which increases the risk of infections. Nutrition given before and during surgery can avoid fasting and has been shown to increase the arginine/asymmetric dimetlhylarginine ratio, a marker of nitric oxide availability, in cardiac tissue and increased concentrations of branched chain amino acids in blood plasma. However, the effect of this new nutritional strategy on organ inflammatory response is unknown. Therefore, we studied the effect of nutrition before and during cardiac surgery on myocardial inflammatory response. In this trial, 32 patients were randomised between enteral, parenteral, and no nutrition supplementation (control) from 2 days before, during, up to 2 days after coronary artery bypass grafting. Both solutions included proteins or amino acids, glucose, vitamins, and minerals. Myocardial atrial tissue was sampled before and after revascularization and was analysed immunohistochemically, subdivided into cardiomyocytic, fatty, and fibrotic areas. Inflammatory cells, especially leukocytes, were present in cardiac tissue in all study groups. No significant differences were found in the myocardial inflammatory response between the enteral, parenteral, and control groups. In conclusion, nutrition given before and during surgery neither stimulates nor diminishes the myocardial inflammatory response in patients undergoing coronary artery bypass grafting. The trial was registered in Netherlands Trial Register (NTR): NTR2183. PMID:26294967

  15. JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats.

    PubMed

    Tao, Zhen; Cheng, Ming; Wang, Shu-Cai; Lv, Wei; Hu, Huai-Qiang; Li, Chuan-Fen; Cao, Bing-Zhen

    2015-01-01

    Heatstroke not only directly induces cell injury, but also causes large amounts of inflammatory mediators release and cells with extensive biological activities to induce a systemic inflammatory response and immune dysfunction. This study aimed to observe the effects of JAK2 inhibitor AG490 on the brain injury and inflammatory responses of rats with systemic heatstroke. Under the light microscope, the hippocampus tissues of rat with heatstroke were edema and apoptotic rate was increased. Up-regulation of malondialdehyde (MDA), nitric oxide synthase (iNOS), reactive oxygen species (ROS) and down-regulation of superoxide dismutase (SOD) were also found after heatstroke in rats, which compared with that of the control group. Heatstroke induced inflammation factors secretions and up-regulated levels of matrix metallopeptidase 2 and 9 (MMP2 and MMP-9) and systemic inflammatory response molecules including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-beta 1 (TNF-β1) and cyclooxygenase-2 (COX-2). However, the JAK2 inhibitor AG490 was significantly attenuated the brain injury and inflammatory responses induced by heatstroke in rats. The survival time of heatstroke rats showed that AG490 notably lived longer than heatstroke rats without AG490 treatment. These findings suggest that AG490 may prevent the occurrence of heatstroke via inhibiting the JAK2/STAT3 pathway and the systemic inflammatory responses. PMID:26261556

  16. JAK2/STAT3 pathway mediating inflammatory responses in heatstroke-induced rats

    PubMed Central

    Tao, Zhen; Cheng, Ming; Wang, Shu-Cai; Lv, Wei; Hu, Huai-Qiang; Li, Chuan-Fen; Cao, Bing-Zhen

    2015-01-01

    Heatstroke not only directly induces cell injury, but also causes large amounts of inflammatory mediators release and cells with extensive biological activities to induce a systemic inflammatory response and immune dysfunction. This study aimed to observe the effects of JAK2 inhibitor AG490 on the brain injury and inflammatory responses of rats with systemic heatstroke. Under the light microscope, the hippocampus tissues of rat with heatstroke were edema and apoptotic rate was increased. Up-regulation of malondialdehyde (MDA), nitric oxide synthase (iNOS), reactive oxygen species (ROS) and down-regulation of superoxide dismutase (SOD) were also found after heatstroke in rats, which compared with that of the control group. Heatstroke induced inflammation factors secretions and up-regulated levels of matrix metallopeptidase 2 and 9 (MMP2 and MMP-9) and systemic inflammatory response molecules including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-beta 1 (TNF-β1) and cyclooxygenase-2 (COX-2). However, the JAK2 inhibitor AG490 was significantly attenuated the brain injury and inflammatory responses induced by heatstroke in rats. The survival time of heatstroke rats showed that AG490 notably lived longer than heatstroke rats without AG490 treatment. These findings suggest that AG490 may prevent the occurrence of heatstroke via inhibiting the JAK2/STAT3 pathway and the systemic inflammatory responses. PMID:26261556

  17. Functional Food Targeting the Regulation of Obesity-Induced Inflammatory Responses and Pathologies

    PubMed Central

    Hirai, Shizuka; Takahashi, Nobuyuki; Goto, Tsuyoshi; Lin, Shan; Uemura, Taku; Yu, Rina; Kawada, Teruo

    2010-01-01

    Obesity is associated with a low-grade systemic chronic inflammatory state, characterized by the abnormal production of pro- and anti-inflammatory adipocytokines. It has been found that immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Obesity-induced inflammation is considered a potential mechanism linking obesity to its related pathologies, such as insulin resistance, cardiovascular diseases, type-2 diabetes, and some immune disorders. Therefore, targeting obesity-related inflammatory components may be a useful strategy to prevent or ameliorate the development of such obesity-related diseases. It has been shown that several food components can modulate inflammatory responses in adipose tissue via various mechanisms, some of which are dependent on peroxisome proliferator-activated receptor γ (PPARγ), whereas others are independent on PPARγ, by attenuating signals of nuclear factor-κB (NF-κB) and/or c-Jun amino-terminal kinase (JNK). In this review, we introduce the beneficial effects of anti-inflammatory phytochemicals that can help prevent obesity-induced inflammatory responses and pathologies. PMID:20508825

  18. Characterization of Inflammatory Response in Acute-on-Chronic Liver Failure and Relationship with Prognosis

    PubMed Central

    Solé, Cristina; Solà, Elsa; Morales-Ruiz, Manuel; Fernàndez, Guerau; Huelin, Patricia; Graupera, Isabel; Moreira, Rebeca; de Prada, Gloria; Ariza, Xavier; Pose, Elisa; Fabrellas, Núria; Kalko, Susana G.; Jiménez, Wladimiro; Ginès, Pere

    2016-01-01

    ACLF is characterized by a systemic inflammatory response, but the cytokines involved in this process have not been well studied. The aim of this study was to characterize the systemic inflammatory response in patients with cirrhosis and ACLF and its relationship with prognosis. Fifty-five patients with cirrhosis, 26 with ACLF, were studied prospectively. Systemic inflammatory response was analyzed by measuring a large array of plasma cytokines by using a multiplex kit. A principal component analysis show noticeable differences between ACLF and decompensated cirrhosis without ACLF. Patients with ACLF had significant abnormal levels of 12 cytokines compared to those without ACLF, including: VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10, RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, and MCP-1. Cytokines showing the most marked relationship with ACLF were VCAM-1 and VEGF-A (AUCROC 0.77; p = 0.001). There was a significant relationship between some of inflammatory mediators and 3-month mortality, particularly VCAM-1, ICAM-1, and GM-CSF (AUCROC>0.7; p < 0.05). Functional Enrichment Analysis showed that inflammatory markers differentially expressed in ACLF patients were enriched in leukocyte migration, particularly monocytes and macrophages, and chemotaxis pathways. In conclusion, ACLF is characterized by a marked inflammatory reaction with activation of mediators of adhesion and migration of leukocytes. The intensity of the inflammatory reaction correlates with prognosis. PMID:27578545

  19. Characterization of Inflammatory Response in Acute-on-Chronic Liver Failure and Relationship with Prognosis.

    PubMed

    Solé, Cristina; Solà, Elsa; Morales-Ruiz, Manuel; Fernàndez, Guerau; Huelin, Patricia; Graupera, Isabel; Moreira, Rebeca; de Prada, Gloria; Ariza, Xavier; Pose, Elisa; Fabrellas, Núria; Kalko, Susana G; Jiménez, Wladimiro; Ginès, Pere

    2016-01-01

    ACLF is characterized by a systemic inflammatory response, but the cytokines involved in this process have not been well studied. The aim of this study was to characterize the systemic inflammatory response in patients with cirrhosis and ACLF and its relationship with prognosis. Fifty-five patients with cirrhosis, 26 with ACLF, were studied prospectively. Systemic inflammatory response was analyzed by measuring a large array of plasma cytokines by using a multiplex kit. A principal component analysis show noticeable differences between ACLF and decompensated cirrhosis without ACLF. Patients with ACLF had significant abnormal levels of 12 cytokines compared to those without ACLF, including: VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10, RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, and MCP-1. Cytokines showing the most marked relationship with ACLF were VCAM-1 and VEGF-A (AUCROC 0.77; p = 0.001). There was a significant relationship between some of inflammatory mediators and 3-month mortality, particularly VCAM-1, ICAM-1, and GM-CSF (AUCROC>0.7; p < 0.05). Functional Enrichment Analysis showed that inflammatory markers differentially expressed in ACLF patients were enriched in leukocyte migration, particularly monocytes and macrophages, and chemotaxis pathways. In conclusion, ACLF is characterized by a marked inflammatory reaction with activation of mediators of adhesion and migration of leukocytes. The intensity of the inflammatory reaction correlates with prognosis. PMID:27578545

  20. Gangliosides trigger inflammatory responses via TLR4 in brain glia.

    PubMed

    Jou, Ilo; Lee, Jee Hoon; Park, Soo Young; Yoon, Hee Jung; Joe, Eun-Hye; Park, Eun Jung

    2006-05-01

    Gangliosides participate in various cellular events of the central nervous system and have been closely implicated in many neuronal diseases. However, the precise molecular mechanisms underlying the pathological activity of gangliosides are poorly understood. Here we report that toll-like receptor 4 (TLR4) may mediate the ganglioside-triggered inflammation in glia, brain resident immune cells. Gangliosides rapidly altered the cell surface expression of TLR4 in microglia and astrocytes within 3 hours. Using TLR4-specific siRNA and a dominant-negative TLR4 gene, we clearly demonstrate the functional importance of TLR4 in ganglioside-triggered activation of glia. Inhibition of TLR4 expression by TLR4-siRNA suppressed nuclear factor (NF)-kappaB-binding activity, NF-kappaB-dependent luciferase activity, and transcription of inflammatory cytokines after exposure to gangliosides. Transient transfection of dominant-negative TLR4 also attenuated NF-kappaB-binding activity and interleukin-6 promoter activity. In contrast, these activities were slightly elevated in cells with wild-type TLR4. In addition, CD14 was required for ganglioside-triggered activation of glia, and lipid raft formation may be associated with ganglioside-stimulated signal propagation. Taken together, these results suggest that TLR4 may provide an explanation for the pathological ability of gangliosides to cause inflammatory conditions in the brain. PMID:16651628

  1. Malarial Pigment Hemozoin and the Innate Inflammatory Response

    PubMed Central

    Olivier, Martin; Van Den Ham, Kristin; Shio, Marina Tiemi; Kassa, Fikregabrail Aberra; Fougeray, Sophie

    2014-01-01

    Malaria is a deadly infectious disease caused by the intraerythrocytic protozoan parasite Plasmodium. The four species of Plasmodium known to affect humans all produce an inorganic crystal called hemozoin (HZ) during the heme detoxification process. HZ is released from the food vacuole into circulation during erythrocyte lysis, while the released parasites further infect additional naive red blood cells. Once in circulation, HZ is rapidly taken up by circulating monocytes and tissue macrophages, inducing the production of pro-inflammatory mediators, such as interleukin-1β (IL-1β). Over the last few years, it has been reported that HZ, similar to uric acid crystals, asbestos, and silica, is able to trigger IL-1β production via the activation of the NOD-like receptor containing pyrin domain 3 (NLRP3) inflammasome complex. Additionally, recent findings have shown that host factors, such as fibrinogen, have the ability to adhere to free HZ and modify its capacity to activate host immune cells. Although much has been discovered regarding NLRP3 inflammasome induction, the mechanism through which this intracellular multimolecular complex is activated remains unclear. In the present review, the most recent discoveries regarding the capacity of HZ to trigger this innate immune complex as well as the impact of HZ on several other inflammatory signaling pathways will be discussed. PMID:24550911

  2. Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages.

    PubMed

    Moore, Sherri M; Holt, Vivian V; Malpass, Lillie R; Hines, Ian N; Wheeler, Michael D

    2015-10-01

    The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. PMID:26105806

  3. Obesity and inflammatory arthritis: impact on occurrence, disease characteristics and therapeutic response

    PubMed Central

    Daïen, Claire I; Sellam, Jérémie

    2015-01-01

    Overweight and obesity are increasing worldwide and now reach about one-third of the world's population. Obesity also involves patients with inflammatory arthritis. Knowing the impact of obesity on rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) is thus an important issue. This article first reviews the epidemiological and clinical data available on obesity in inflammatory rheumatic diseases, that is, its impact on incident disease, disease characteristics and the therapeutic response. The second part of this review gives an overview of the factors potentially involved in the specifics of inflammatory arthritis in patients with obesity, such as limitations in the clinical assessment, diet, microbiota and adipokines. PMID:26509048

  4. The effects of levan on the acute inflammatory response.

    PubMed Central

    Sedgwick, A. D.; Rutman, A.; Sin, Y. M.; Mackay, A. R.; Willoughby, D. A.

    1984-01-01

    The fructose polymer levan has been shown to affect the accumulation of leucocytes in inflammatory lesions. The present study has investigated the effect of levan on experimental pleurisy induced by carrageenan and calcium pyrophosphate dihydrate (CPPD) crystals. Total pleural polymorphonuclear leucocyte counts and exudate volumes were significantly reduced by levan treatment. We were, however, unable to detect any effect on mononuclear cell numbers. Furthermore, levan treatment significantly reduced peripheral leucocyte numbers. The counter-irritant activity of levan was compared with that of a known counter-irritant, dextran. The ability of levan to reduce pleural polymorph numbers and exudate volume could not be accounted for totally by counter-irritation. Studies using an in-vitro leucocyte adhesion assay system indicate that levan affects leucocyte adhesion to vascular endothelium. PMID:6201184

  5. Inflammatory response and neuronal necrosis in rats with cerebral ischemia

    PubMed Central

    Wu, Lingfeng; Zhang, Kunnan; Hu, Guozhu; Yan, Haiyu; Xie, Chen; Wu, Xiaomu

    2014-01-01

    In the middle cerebral artery occlusion model of ischemic injury, inflammation primarily occurs in the infarct and peripheral zones. In the ischemic zone, neurons undergo necrosis and apoptosis, and a large number of reactive microglia are present. In the present study, we investigated the pathological changes in a rat model of middle cerebral artery occlusion. Neuronal necrosis appeared 12 hours after middle cerebral artery occlusion, and the peak of neuronal apoptosis appeared 4 to 6 days after middle cerebral artery occlusion. Inflammatory cytokines and microglia play a role in damage and repair after middle cerebral artery occlusion. Serum intercellular cell adhesion molecule-1 levels were positively correlated with the permeability of the blood-brain barrier. These findings indicate that intercellular cell adhesion molecule-1 may be involved in blood-brain barrier injury, microglial activation, and neuronal apoptosis. Inhibiting blood-brain barrier leakage may alleviate neuronal injury following ischemia. PMID:25422636

  6. Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses.

    PubMed

    Provoost, Sharen; De Grove, Katrien C; Fraser, Graeme L; Lannoy, Vincent J; Tournoy, Kurt G; Brusselle, Guy G; Maes, Tania; Joos, Guy F

    2016-02-15

    Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP-enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation. PMID:26773141

  7. Sirt2 suppresses inflammatory responses in collagen-induced arthritis

    SciTech Connect

    Lin, Jiangtao; Sun, Bing; Jiang, Chuanqiang; Hong, Huanyu; Zheng, Yanping

    2013-11-29

    Highlights: •Sirt2 expression decreases in collagen-induced arthritis (CIA). •Sirt2 knockout aggravates severity of arthritis in mice with CIA. •Sirt2 knockout increases levels of pro-inflammatory factors in the serum. •Sirt2 deacetylates p65 and inhibits pro-inflammatory factors expression. •Sirt2 rescue abates severity of arthritis in mice with CIA. -- Abstract: Arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications and early death. However, the underling mechanisms of arthritis are still unclear. Sirtuins are a NAD{sup +}-dependent class III deacetylase family, and regulate cellular stress, inflammation, genomic stability, carcinogenesis, and energy metabolism. Among the sirtuin family members, Sirt1 and Sirt6 are critically involved in the development of arthritis. It remains unknown whether other sirtuin family members participate in arthritis. Here in this study, we demonstrate that Sirt2 inhibits collagen-induced arthritis (CIA) using in vivo and in vitro evidence. The protein and mRNA levels of Sirt2 significantly decreased in joint tissues of mice with CIA. When immunized with collagen, Sirt2-KO mice showed aggravated severity of arthritis based on clinical scores, hind paw thickness, and radiological and molecular findings. Mechanically, Sirt2 deacetylated p65 subunit of nuclear factor-kappa B (NF-κB) at lysine 310, resulting in reduced expression of NF-κB-dependent genes, including interleukin 1β (IL-1β), IL-6, monocyte chemoattractant protein 1(MCP-1), RANTES, matrix metalloproteinase 9 (MMP-9) and MMP-13. Importantly, our rescue experiment showed that Sirt2 re-expression abated the severity of arthritis in Sirt2-KO mice. Those findings strongly indicate Sirt2 as a considerably inhibitor of the development of arthritis.

  8. Glucocorticoid-Induced Attenuation of the Inflammatory Response in Zebrafish.

    PubMed

    Chatzopoulou, Antonia; Heijmans, Jeroen P M; Burgerhout, Erik; Oskam, Nienke; Spaink, Herman P; Meijer, Annemarie H; Schaaf, Marcel J M

    2016-07-01

    Glucocorticoids are steroid hormones that are secreted upon stress. Their effects are mediated by the glucocorticoid receptor, which acts as a transcription factor. Because the antiinflammatory activity of glucocorticoids has been well established, they are widely used clinically to treat many inflammatory and immune-related diseases. However, the exact specificity, mechanisms, and level of regulation of different inflammatory pathways have not been fully elucidated. In the present study, a tail fin amputation assay was used in 3-day-old zebrafish larvae to study the immunomodulatory effects of the synthetic glucocorticoid beclomethasone. First, a transcriptome analysis was performed, which showed that upon amputation mainly immune-related genes are regulated. This regulation was inhibited by beclomethasone for 86% of regulated genes. For two immune-related genes, tlr4bb and alox5ap, the amputation-induced increase was not attenuated by beclomethasone. Alox5ap is involved in eicosanoid biosynthesis, but the increase in leukotriene B4 concentration upon amputation was abolished, and lipoxin A4 levels were unaffected by beclomethasone. Furthermore, we studied the migration of neutrophils and macrophages toward the wound site. Our results show that amputation induced migration of both types of leukocytes and that this migration was dependent on de novo protein synthesis. Beclomethasone treatment attenuated the migratory behavior of neutrophils in a glucocorticoid receptor-dependent manner but left the migration of macrophages unaffected. In conclusion, beclomethasone has a dramatic inhibitory effect on the amputation-induced proinflammatory gene regulation, and this is reflected in an inhibition of the neutrophil migration but not the migration of macrophages, which are likely to be involved in inflammation resolution. PMID:27219276

  9. The Laminin Response in Inflammatory Bowel Disease: Protection or Malignancy?

    PubMed Central

    Spenlé, Caroline; Lefebvre, Olivier; Lacroute, Joël; Méchine-Neuville, Agnès; Barreau, Frédérick; Blottière, Hervé M.; Duclos, Bernard; Arnold, Christiane; Hussenet, Thomas; Hemmerlé, Joseph; Gullberg, Donald; Kedinger, Michèle; Sorokin, Lydia; Orend, Gertraud; Simon-Assmann, Patricia

    2014-01-01

    Laminins (LM), basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD) are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS) combined or not with a carcinogen (AOM) in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach. PMID:25347196

  10. Roles of Toll-like receptors 2 and 6 in the inflammatory response to Mycoplasma gallisepticum infection in DF-1 cells and in chicken embryos.

    PubMed

    Tian, Wei; Zhao, Chengcheng; Hu, Qingchuang; Sun, Jianjun; Peng, Xiuli

    2016-06-01

    While Mycoplasma gallisepticum (MG) is a major pathogen that causes chronic respiratory diseases in chicken, the molecular mechanism of MG infection is not clear. In this study, we investigated the roles of Toll-like receptor 2 (TLR2) and 6 (TLR6) in MG infection. We found that TLR2 type 2 (TLR2-2) and TLR6 had differential expressions in chicken embryo fibroblasts (DF-1 cells), where TLR6 was highly expressed, but TLR2-2 was barely expressed. Upon MG infection, TLR6 expression was upregulated, followed by upregulation of downstream factors, MyD88, NF-κB, IL2, IL6, and TNF-α. Knockdown of TLR6 expression by shRNA abolished the MG-induced inflammatory responses. More interestingly, in the presence of TLR6, TLR2-2 didn't respond to MG infection in DF-1 cells. When TLR6 was knocked down by shRNA, however, TLR2 was upregulated upon MG infection, which was followed by upregulation of proinflammatory genes. Finally, we tested effects of the MG infection on expression of TLR2-2 and TLR6 in the lungs and trachea tissues of chicken embryos. We found both TLR2-2 and TLR6 were upregulated upon MG infection, followed by upregulation of the downstream NF-κB-mediated inflammatory responses. This study was the first to report the differential roles of TLR2-2 and TLR6 in MG-infected DF-1 cells and chicken embryos. PMID:26797426

  11. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    PubMed Central

    Vamvakopoulos, Nicholas V.

    1995-01-01

    This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2) a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system. PMID:18475634

  12. The Biochemical Origin of Pain: The origin of all Pain is Inflammation and the Inflammatory Response. PART 2 of 3 –Inflammatory Profile of Pain Syndromes

    PubMed Central

    2009-01-01

    Every pain syndrome has an inflammatory profile consisting of the inflammatory mediators that are present in the pain syndrome. The inflammatory profile may have variations from one person to another and may have variations in the same person at different times. The key to treatment of Pain Syndromes is an understanding of their inflammatory profile. Pain syndromes may be treated medically or surgically. The goal should be inhibition or suppression of production of the inflammatory mediators and inhibition, suppression or modulation of neuronal afferent and efferent (motor) transmission. A successful outcome is one that results in less inflammation and thus less pain. We hereby describe the inflammatory profile for several pain syndromes including arthritis, back pain, neck pain, fibromyalgia, interstitial cystitis, migraine, neuropathic pain, complex regional pain syndrome / reflex sympathetic dystrophy (CRPS/RSD), bursitis, shoulder pain and vulvodynia. These profiles are derived from basic science and clinical research performed in the past by numerous investigators and will be updated in the future by new technologies such as magnetic resonance spectroscopy. Our unifying theory or law of pain states: The origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing

  13. Role of inflammatory cytokines in the response of solid cancers to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai; Cecic, Ivana; Dougherty, Graeme J.

    2001-04-01

    Photodynamic therapy (PDT) elicits a strong acute inflammatory response that has both local and systemic (acute phase response) attributes. The insult mediated by PDT-induced oxidative stress at the targeted site triggers a complex multifactorial response engaging host defence mechanisms associated with the inflammatory process to participate in the eradication of the treated tumor. Inflammatory cytokines are important mediators of critical events in this process as they regulate the activity of inflammatory, endothelial and other cells. The initial stimulus for enhanced production and release of cytokines likely originates from several types of events, such as activated transcription factors and complement deposition. The PDT-induced complement activation appears to be directly linked to the enhanced expression of various cytokines, including chemokines such as KC (in mouse models), and classic inflammatory cytokines such as IL-1β, TNF-α , IL-6 and IL-10. A variety of interventions that modulate the activity of particular cytokines performed in conjunction with PDT were shown to influence the therapy outcome. The treatments such as using blocking antibodies and local or systemic cytokine delivery may either reduce or dramatically improve the curative effect of PDT. The inflammatory and related cytokines that at present appear particularly interesting and merit further investigation for use as adjuvants to PDT are IL-3, IL-8, IL-15, TNF-α, IFN-γ, G-CSF and GM-CSF.

  14. Maternal sleep deprivation inhibits hippocampal neurogenesis associated with inflammatory response in young offspring rats.

    PubMed

    Zhao, Qiuying; Peng, Cheng; Wu, Xiaohui; Chen, Yubo; Wang, Cheng; You, Zili

    2014-08-01

    Although sleep complaints are very common among pregnant women, the potential adverse effects of sleep disturbance on the offspring are not well studied. Growing evidence suggests that maternal stress can induce an inflammatory environment on the fetal development. But people are not sure about the consequences of prenatal stress such as the inflammatory responses induced by maternal sleep deprivation (MSD). In the present study, we investigated the effects of MSD on long-term behavioral and cognitive consequences in offspring and its underlying inflammatory response pathway. The pregnant Wistar rats received prolonged sleep deprivation (72h) on gestational day (GD) 4, 9, and 18, respectively. The post-natal day (PND) 21 offspring showed impaired hippocampus-dependent spatial learning and memory in the Morris Water Maze task and anhedonia in sucrose preference experiment. Quantification of BrdU(+) and DCX(+) cells revealed a significant decrease in hippocampus neurogenesis in prepuberty offspring, especially for the late MSD (GD 18) group. Real-time RT-PCR showed that after MSD, the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNFα) increased in the hippocampus of offspring on PND 1, 7, 14 and 21, whereas anti-inflammatory cytokine IL-10 reduced at the same time. Immunofluorescence found that the cells of activated microglia were higher in the brains of MSD offspring. Taken together, these results suggested that the MSD-induced inflammatory response is an important factor for neurogenesis impairment and neurobehavioral outcomes in prepuberty offspring. PMID:24769004

  15. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses

    PubMed Central

    Madera, Laurence; Greenshields, Anna; Coombs, Melanie R. Power; Hoskin, David W.

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated enhanced production of pro-inflammatory cytokines tumor necrosis factor α, interleukin-6, and CCL2 in response to lipopolysaccharide (LPS) while production of interleukin-10 remained unchanged. The increased LPS-induced production of pro-inflammatory cytokines was transient and correlated with enhanced cytokine production in response to other Toll-like receptor agonists, including peptidoglycan and flagellin. In addition, 4T1-conditioned BMDMs exhibited strengthened LPS-induced nitric oxide production and enhanced phagocytosis of Escherichia coli. 4T1-mediated augmentation of macrophage responses to LPS was partially dependent on the NFκB pathway, macrophage-colony stimulating factor, and actin polymerization, as well as the presence of 4T1-secreted extracellular vesicles. Furthermore, peritoneal macrophages obtained from 4T1 tumor-bearing mice displayed enhanced pro-inflammatory cytokine production in response to LPS. These results suggest that uptake of 4T1-secreted factors and actin-mediated ingestion of 4T1-secreted exosomes by macrophages cause a transient enhancement of innate inflammatory responses. Mammary carcinoma-mediated regulation of innate immunity may have significant implications for our understanding of host defense and cancer progression. PMID:26177198

  16. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses.

    PubMed

    Madera, Laurence; Greenshields, Anna; Coombs, Melanie R Power; Hoskin, David W

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated enhanced production of pro-inflammatory cytokines tumor necrosis factor α, interleukin-6, and CCL2 in response to lipopolysaccharide (LPS) while production of interleukin-10 remained unchanged. The increased LPS-induced production of pro-inflammatory cytokines was transient and correlated with enhanced cytokine production in response to other Toll-like receptor agonists, including peptidoglycan and flagellin. In addition, 4T1-conditioned BMDMs exhibited strengthened LPS-induced nitric oxide production and enhanced phagocytosis of Escherichia coli. 4T1-mediated augmentation of macrophage responses to LPS was partially dependent on the NFκB pathway, macrophage-colony stimulating factor, and actin polymerization, as well as the presence of 4T1-secreted extracellular vesicles. Furthermore, peritoneal macrophages obtained from 4T1 tumor-bearing mice displayed enhanced pro-inflammatory cytokine production in response to LPS. These results suggest that uptake of 4T1-secreted factors and actin-mediated ingestion of 4T1-secreted exosomes by macrophages cause a transient enhancement of innate inflammatory responses. Mammary carcinoma-mediated regulation of innate immunity may have significant implications for our understanding of host defense and cancer progression. PMID:26177198

  17. Inflammatory Response Influences Treatment of Localized Aggressive Periodontitis.

    PubMed

    Allin, N; Cruz-Almeida, Y; Velsko, I; Vovk, A; Hovemcamp, N; Harrison, P; Huang, H; Aukhil, I; Wallet, S M; Shaddox, L M

    2016-06-01

    We previously reported a systemic hyperinflammatory response to bacterial lipopolysaccharide (LPS) in children with localized aggressive periodontitis (LAP). Additionally, different levels of this response were observed within the LAP group. It is unknown whether this hyperinflammatory response influences the clinical response to periodontal treatment in these children. Therefore, the goal of this study was to evaluate the influence of LPS responsiveness present prior to treatment on the clinical response to treatment within the LAP cohort. Prior to treatment, peripheral blood was collected from 60 African American participants aged 5 to 21 y, free of systemic diseases, and diagnosed with LAP. Blood was stimulated with ultrapure LPS from Escherichia coli, and Luminex assays were performed to quantify 14 cytokine/chemokine levels. Principal component and cluster analyses were used to find patterns of cytokine/chemokine expression among participants and subdivide them into clusters. Three distinct clusters emerged among LAP participants: a high responder group (high level of response for INFg, IL6, and IL12p40), a mixed responder group (low for some and high for other cytokines/chemokines), and a low responder group (low overall cytokine/chemokine response). Periodontal clinical parameters were compared among these groups prior to and 3, 6, and 12 mo following treatment with mechanical debridement and systemic antibiotics. High responders presented the lowest reductions in clinical parameters after treatment, whereas the low responders presented the highest reductions. In our LAP participants, distinct patterns of LPS response were significantly predictive of changes in clinical parameters after treatment. Future studies are needed to evaluate the underlying mechanisms predicting the heterogeneity of LAP activity, severity, and response to treatment (ClinicalTrials.gov NCT01330719). PMID:26917438

  18. Soluble Mediators in Platelet Concentrates Modulate Dendritic Cell Inflammatory Responses in an Experimental Model of Transfusion.

    PubMed

    Perros, Alexis J; Christensen, Anne-Marie; Flower, Robert L; Dean, Melinda M

    2015-10-01

    The transfusion of platelet concentrates (PCs) is widely used to treat thrombocytopenia and severe trauma. Ex vivo storage of PCs is associated with a storage lesion characterized by partial platelet activation and the release of soluble mediators, such as soluble CD40 ligand (sCD40L), RANTES, and interleukin (IL)-8. An in vitro whole blood culture transfusion model was employed to assess whether mediators present in PC supernatants (PC-SNs) modulated dendritic cell (DC)-specific inflammatory responses (intracellular staining) and the overall inflammatory response (cytometric bead array). Lipopolysaccharide (LPS) was included in parallel cultures to model the impact of PC-SNs on cell responses following toll-like receptor-mediated pathogen recognition. The impact of both the PC dose (10%, 25%) and ex vivo storage period was investigated [day 2 (D2), day 5 (D5), day 7 (D7)]. PC-SNs alone had minimal impact on DC-specific inflammatory responses and the overall inflammatory response. However, in the presence of LPS, exposure to PC-SNs resulted in a significant dose-associated suppression of the production of DC IL-12, IL-6, IL-1α, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein (MIP)-1β and storage-associated suppression of the production of DC IL-10, TNF-α, and IL-8. For the overall inflammatory response, IL-6, TNF-α, MIP-1α, MIP-1β, and inflammatory protein (IP)-10 were significantly suppressed and IL-8, IL-10, and IL-1β significantly increased following exposure to PC-SNs in the presence of LPS. These data suggest that soluble mediators present in PCs significantly suppress DC function and modulate the overall inflammatory response, particularly in the presence of an infectious stimulus. Given the central role of DCs in the initiation and regulation of the immune response, these results suggest that modulation of the DC inflammatory profile is a probable mechanism contributing to transfusion-related complications. PMID:26133961

  19. Rat lung inflammatory responses after in vivo and in vitro exposure to various stone particles.

    PubMed

    Becher, R; Hetland, R B; Refsnes, M; Dahl, J E; Dahlman, H J; Schwarze, P E

    2001-09-01

    Rat lung alveolar macrophages and type 2 cells were exposed for 20 h in vitro to various stone particles with differing contents of metals and minerals (a type of mylonite, gabbro, feldspar, and quartz). The capability to induce the release of the inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2) was investigated. We found marked differences in potency between the various particles, with mylonite being most potent overall, followed by gabbro, and with feldspar and quartz having an approximately similar order of lower potency. The results also demonstrated differences in cytokine release pattern between the two cell types. For all particle types including quartz, type 2 cells showed the most marked increase in MIP-2 and IL-6 secretion, whereas the largest increase in TNF-alpha release was observed in macrophages. To investigate possible correlations between in vitro and in vivo inflammatory responses, rats were instilled with the same types of particles and bronchoalveolar lavage (BAL) fluid was collected after 20 h. The results demonstrated a correlation between the in vitro cytokine responses and the number of neutrophilic cells in the BAL fluid. The BAL fluid also showed a strong MIP-2 response to mylonite. However, this was the only particle type to give a significant cytokine response in the BAL fluid. We further examined whether a similar graded inflammatory response would be continued in type 2 cells and alveolar macrophages isolated from the exposed animals. Again a differential cytokine release pattern was observed between type 2 cells and macrophages, although the order of potency between particle types was altered. In conclusion, various stone particles caused differential inflammatory responses after both in vitro and in vivo exposure, with mylonite being the most potent stone particle. The results suggest the alveolar type 2 cell to be an important participant in the

  20. Involvement of glycosphingolipid-enriched lipid rafts in inflammatory responses.

    PubMed

    Iwabuchi, Kazuhisa

    2015-01-01

    Glycosphingolipids (GSLs) are membrane components consisting of hydrophobic ceramide and hydrophilic sugar moieties. GSLs cluster with cholesterol in cell membranes to form GSL-enriched lipid rafts. Biochemical analyses have demonstrated that GSL-enriched lipid rafts contain several kinds of transducer molecules, including Src family kinases. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms, is highly expressed on the plasma membranes of human phagocytes, and forms lipid rafts containing the Src family tyrosine kinase Lyn. LacCer-enriched lipid rafts mediate immunological and inflammatory reactions, including superoxide generation, chemotaxis, and non-opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. LacCer also serves as a signal transduction molecule for functions mediated by CD11b/CD18-integrin (αM/β2-integrin, CR3, Mac-1), as well as being associated with several key cellular processes. LacCer recruits PCKα/ε and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and their adhesion to endothelial cells, as well as regulating β1-integrin clustering and endocytosis on cell surfaces. This review describes the organizational and inflammation-related functions of LacCer-enriched lipid rafts. PMID:25553454

  1. Rosmarinus officinalis Extract Suppresses Propionibacterium acnes–Induced Inflammatory Responses

    PubMed Central

    Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu

    2013-01-01

    Abstract Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes–induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes–stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes–induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes–induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes–induced inflammation. PMID:23514231

  2. Comparison of Inflammatory Response to Transgastric and Transcolonic NOTES

    PubMed Central

    Hucl, Tomas; Benes, Marek; Kocik, Matej; Splichalova, Alla; Maluskova, Jana; Krak, Martin; Lanska, Vera; Heczkova, Marie; Kieslichova, Eva; Oliverius, Martin; Spicak, Julius

    2016-01-01

    Aims. The aim of our study was to determine the physiologic impact of NOTES and to compare the transgastric and transcolonic approaches. Methods. Thirty pigs were randomized to transgastric, transcolonic, or laparoscopic peritoneoscopy. Blood was drawn and analyzed for C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, IL-6, WBCs, and platelets. Results. Endoscopic closure with an OTSC was successful in all 20 animals. The postoperative course was uneventful in all animals. CRP values rose on day 1 in all animals and slowly declined to baseline levels on day 14 with no differences between the groups (P > 0.05, NS). The levels of TNF-α were significantly increased in the transcolonic group (P < 0.01); however this difference was already present prior to the procedure and remained unchanged. No differences were observed in IL1-β and IL-6 values. There was a temporary rise of WBC on day 1 and of platelets on day 7 in all groups (P > 0.05, NS). Conclusions. Transgastric, transcolonic, and laparoscopic peritoneoscopy resulted in similar changes in systemic inflammatory markers. Our findings do not support the assumption that NOTES is less invasive than laparoscopy. PMID:27403157

  3. Rosmarinus officinalis extract suppresses Propionibacterium acnes-induced inflammatory responses.

    PubMed

    Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu; Tsai, Po-Jung

    2013-04-01

    Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes-induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes-stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes-induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes-induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes-induced inflammation. PMID:23514231

  4. Comparison of Inflammatory Response to Transgastric and Transcolonic NOTES.

    PubMed

    Hucl, Tomas; Benes, Marek; Kocik, Matej; Splichalova, Alla; Maluskova, Jana; Krak, Martin; Lanska, Vera; Heczkova, Marie; Kieslichova, Eva; Oliverius, Martin; Spicak, Julius

    2016-01-01

    Aims. The aim of our study was to determine the physiologic impact of NOTES and to compare the transgastric and transcolonic approaches. Methods. Thirty pigs were randomized to transgastric, transcolonic, or laparoscopic peritoneoscopy. Blood was drawn and analyzed for C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, IL-6, WBCs, and platelets. Results. Endoscopic closure with an OTSC was successful in all 20 animals. The postoperative course was uneventful in all animals. CRP values rose on day 1 in all animals and slowly declined to baseline levels on day 14 with no differences between the groups (P > 0.05, NS). The levels of TNF-α were significantly increased in the transcolonic group (P < 0.01); however this difference was already present prior to the procedure and remained unchanged. No differences were observed in IL1-β and IL-6 values. There was a temporary rise of WBC on day 1 and of platelets on day 7 in all groups (P > 0.05, NS). Conclusions. Transgastric, transcolonic, and laparoscopic peritoneoscopy resulted in similar changes in systemic inflammatory markers. Our findings do not support the assumption that NOTES is less invasive than laparoscopy. PMID:27403157

  5. Host Transcription Factors in the Immediate Pro-Inflammatory Response to the Parasitic Mite Psoroptes ovis

    PubMed Central

    Burgess, Stewart T. G.; McNeilly, Tom N.; Watkins, Craig A.; Nisbet, Alasdair J.; Huntley, John F.

    2011-01-01

    Background Sheep scab, caused by infestation with the ectoparasitic mite Psoroptes ovis, results in the rapid development of cutaneous inflammation and leads to the crusted skin lesions characteristic of the disease. We described previously the global host transcriptional response to infestation with P. ovis, elucidating elements of the inflammatory processes which lead to the development of a rapid and profound immune response. However, the mechanisms by which this response is instigated remain unclear. To identify novel methods of intervention a better understanding of the early events involved in triggering the immune response is essential. The objective of this study was to gain a clearer understanding of the mechanisms and signaling pathways involved in the instigation of the immediate pro-inflammatory response. Results Through a combination of transcription factor binding site enrichment and pathway analysis we identified key roles for a number of transcription factors in the instigation of cutaneous inflammation. In particular, defined roles were elucidated for the transcription factors NF-kB and AP-1 in the orchestration of the early pro-inflammatory response, with these factors being implicated in the activation of a suite of inflammatory mediators. Conclusions Interrogation of the host temporal response to P. ovis infestation has enabled the further identification of the mechanisms underlying the development of the immediate host pro-inflammatory response. This response involves key regulatory roles for the transcription factors NF-kB and AP-1. Pathway analysis demonstrated that the activation of these transcription factors may be triggered following a host LPS-type response, potentially involving TLR4-signalling and also lead to the intriguing possibility that this could be triggered by a P. ovis allergen. PMID:21915322

  6. Impact of nutrition on immune function and the inflammatory response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The review utilizes data on three micronutrients (vitamin A, zinc and iron), anthropometrically defined undernutrition (stunting, wasting and underweight) and obesity to evaluate the effect on immune function, recovery of immune function in response to nutritional interventions, related health outco...

  7. Triclosan Alters Anti-microbial and Inflammatory Responses of Epithelial Cells

    PubMed Central

    Wallet, Mark A.; Calderon, Nadia L.; Alonso, Tess R.; Choe, Christina S.; Catalfamo, Dana L.; Lalane, Charles J.; Neiva, Kathleen G.; Panagakos, Foti; Wallet, Shannon M.

    2012-01-01

    Periodontal diseases are a class of pathologies wherein oral microbes induce harmful immune responses in a susceptible host. Therefore, an agent which can both reduce microbial burden and lessen pathogenesis of localized inflammation would have beneficial effects in periodontal disease. 2,4,4-trichloro-2-hydroxydiphenyl-ether [triclosan] is currently used in oral care products due to broad spectrum anti-microbial and anti-inflammatory properties. Objective To determine effects of triclosan on the response of oral epithelial cells to stimulation with the inflammatory microbial product lipopolysaccharide [LPS], a ligand for toll-like receptor 4 [TLR4]. Materials/Methods Primary human oral epithelial cells were stimulated with LPS in the presence and/or absence of triclosan after which expression of pro-inflammatory cytokines, β-defensins, micro-RNAs [miRNAs] or TLR signaling pathway proteins were evaluated. Results Here we demonstrate that triclosan is a potent inhibitor of oral epithelial cell LPS-induced pro-inflammatory responses by inducing miRNA regulation of the TLR-signaling pathway. Triclosan was not a pan-suppresser of oral epithelial cell responses as β-defensin 2 [βD2] and βD3 were upregulated by triclosan following LPS-stimulation. Conclusions These data demonstrate both a novel anti-microbial mechanism by which triclosan improves plaque control and an additional anti-inflammatory property which could have beneficial effects in periodontal disease resolution. PMID:24079913

  8. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects.

    PubMed

    Andreasen, Anne Sofie; Larsen, Nadja; Pedersen-Skovsgaard, Theis; Berg, Ronan M G; Møller, Kirsten; Svendsen, Kira Dynnes; Jakobsen, Mogens; Pedersen, Bente Klarlund

    2010-12-01

    According to animal studies, intake of probiotic bacteria may improve glucose homeostasis. We hypothesised that probiotic bacteria improve insulin sensitivity by attenuating systemic inflammation. Therefore, the effects of oral supplementation with the probiotic bacterium Lactobacillus acidophilus NCFM on insulin sensitivity and the inflammatory response were investigated in subjects with normal or impaired insulin sensitivity. In a double-blinded, randomised fashion, forty-five males with type 2 diabetes, impaired or normal glucose tolerance were enrolled and allocated to a 4-week treatment course with either L. acidophilus NCFM or placebo. L. acidophilus was detected in stool samples by denaturating gradient gel electrophoresis and real-time PCR. Separated by the 4-week intervention period, two hyperinsulinaemic-euglycaemic clamps were performed to estimate insulin sensitivity. Furthermore, the systemic inflammatory response was evaluated by subjecting the participants to Escherichia coli lipopolysaccharide injection (0·3 ng/kg) before and after the treatment course. L. acidophilus NCFM was detected in 75 % of the faecal samples after treatment with the probiotic bacterium. Insulin sensitivity was preserved among volunteers in the L. acidophilus NCFM group, whereas it decreased in the placebo group. Both baseline inflammatory markers and the systemic inflammatory response were, however, unaffected by the intervention. In conclusion, intake of L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo, but did not affect the systemic inflammatory response. PMID:20815975

  9. Effects of gelsolin on macrophage inflammatory responses to orthopaedic implant wear debris.

    PubMed

    Mihalko, William M; Djenderedjian, Lev; Cheema, Paramjeet S; Smith, Richard

    2014-01-01

    The local effects of implant wear debris on surrounding tissue has been a major focus of many investigators. Although there have been improvements in implants, significant numbers of revision surgeries are performed to address these issues. Gelsolin (GSN) is a protein in the cytoplasm and circulating serum involved in actin breakdown as well as anti-inflammatory processes. In this study, we tested the hypothesis that GSN in the presence of wear debris in vitro decreases the inflammatory response of a human monocyte cell line. We utilized titanium-, polyethylene-, and cobalt-characterized wear particles in a 1:100 and a 1:500 cell-to-particle ratios in the presence of a low (0.2 µM) and normal (2.0 µM) concentrations of GSN and compared the inflammatory response to cells without GSN exposure. The results show that IL-6, IL-1, TNF-α, and PGE₂ all increased with higher concentrations of GSN. Although the anti-inflammatory properties of GSN were not seen in this in vitro experiment, it has previously been shown that GSN does affect the inflammatory response of monocytes to orthopedic implant wear debris. The dose-response curve for GSN may have a bimodal profile, which should be further investigated. PMID:24941406

  10. An Update on the Inflammatory Response after Endovascular Repair for Abdominal Aortic Aneurysm

    PubMed Central

    Arnaoutoglou, Eleni; Kouvelos, George; Koutsoumpelis, Andreas; Patelis, Nikolaos; Lazaris, Andreas; Matsagkas, Miltiadis

    2015-01-01

    Postimplantation syndrome (PIS) is the clinical and biochemical expression of an inflammatory response following endovascular repair of an aortic aneurysm (EVAR). The goal of this review is to provide an update on the inflammatory response after endovascular repair of abdominal aortic aneurysm, discussing its causes and effects on the clinical outcome of the patient. PIS concerns nearly one-third of patients after EVAR. It is generally a benign condition, although in some patients it may negatively affect outcome. The different definitions and conclusions drawn from several studies reveal that PIS needs to be redefined with standardized diagnostic criteria. The type of the endograft's material seems to play a role in the inflammatory response. Future studies should focus on a better understanding of the underlying pathophysiology, predictors, and risk factors as well as determining whether effective preventive strategies are necessary. PMID:26166953

  11. Guggulsterone Attenuated Lipopolysaccharide-Induced Inflammatory Responses in Mouse Inner Medullary Collecting Duct-3 Cells.

    PubMed

    Kim, Dong-Goo; Bae, Gi-Sang; Jo, Il-Joo; Choi, Sun-Bok; Kim, Myoung-Jin; Jeong, Jun-Hyeok; Kang, Dae-Gil; Lee, Ho-Sub; Song, Ho-Joon; Park, Sung-Joo

    2016-02-01

    Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection. PMID:26260258

  12. Tormentic Acid Inhibits IL-1β-Induced Inflammatory Response in Human Osteoarthritic Chondrocytes.

    PubMed

    Yang, Yang; Wang, Yawei; Wang, Yumin; Zhao, Meng; Jia, Haobo; Li, Bing; Xing, Dan

    2016-06-01

    The pro-inflammatory cytokine interleukin-1beta (IL-1β) plays critical roles in pathogenesis of osteoarthritis (OA). Tormentic acid (TA), a triterpene isolated from Rosa rugosa, has anti-inflammatory activity. However, the anti-inflammatory effect of TA on OA is still unclear. So, in the present study, we examined the effect of TA on IL-1β-induced inflammatory response in primary human OA chondrocytes. Our results demonstrated that TA significantly decreased the IL-1β-stimulated expression of matrix metalloproteinase-3 (MMP-3) and MMP-13. It also inhibited the IL-1β-induced expression of inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as the production of NO and prostaglandin E2 (PGE2) in human OA chondrocytes. Furthermore, TA greatly inhibited the IL-1β-induced NF-κB activation. In conclusion, this study is the first to demonstrate the anti-inflammatory activity of TA in human OA chondrocytes. TA significantly inhibits the IL-1β-induced inflammatory response by suppressing the NF-κB signaling pathway. Thus, TA may be a potential agent in the treatment of OA. PMID:27102898

  13. Macrophage-mediated inflammatory response decreases mycobacterial survival in mouse MSCs by augmenting NO production

    PubMed Central

    Yang, Kun; Wu, Yongjian; Xie, Heping; Li, Miao; Ming, Siqi; Li, Liyan; Li, Meiyu; Wu, Minhao; Gong, Sitang; Huang, Xi

    2016-01-01

    Mycobacterium tuberculosis (MTB) is a hard-to-eradicate intracellular microbe, which escapes host immune attack during latent infection. Recent studies reveal that mesenchymal stem cells (MSCs) provide a protective niche for MTB to maintain latency. However, the regulation of mycobacterial residency in MSCs in the infectious microenvironment remains largely unknown. Here, we found that macrophage-mediated inflammatory response during MTB infection facilitated the clearance of bacilli residing in mouse MSCs. Higher inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production were observed in mouse MSCs under macrophage-mediated inflammatory circumstance. Blocking NO production in MSCs increased the survival of intracellular mycobacteria, indicating NO-mediated antimycobacterial activity. Moreover, both nuclear factor κB (NF-κB) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways were involved in iNOS expression and NO production in inflammatory microenvironment. Furthermore, pro-inflammatory cytokine interleukin-1β could trigger NO production in MSCs and exert anti-mycobacterial activity via NF-κB signaling pathway. Neutralization of interleukin-1β in macrophage-mediated inflammatory microenvironment dampened the ability of mouse MSCs to produce NO. Together, our findings demonstrated that macrophage-mediated inflammatory response during mycobacterial infection promotes the clearance of bacilli in mouse MSCs by increasing NO production, which may provide a better understanding of latent MTB infection. PMID:27251437

  14. Macrophage-mediated inflammatory response decreases mycobacterial survival in mouse MSCs by augmenting NO production.

    PubMed

    Yang, Kun; Wu, Yongjian; Xie, Heping; Li, Miao; Ming, Siqi; Li, Liyan; Li, Meiyu; Wu, Minhao; Gong, Sitang; Huang, Xi

    2016-01-01

    Mycobacterium tuberculosis (MTB) is a hard-to-eradicate intracellular microbe, which escapes host immune attack during latent infection. Recent studies reveal that mesenchymal stem cells (MSCs) provide a protective niche for MTB to maintain latency. However, the regulation of mycobacterial residency in MSCs in the infectious microenvironment remains largely unknown. Here, we found that macrophage-mediated inflammatory response during MTB infection facilitated the clearance of bacilli residing in mouse MSCs. Higher inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production were observed in mouse MSCs under macrophage-mediated inflammatory circumstance. Blocking NO production in MSCs increased the survival of intracellular mycobacteria, indicating NO-mediated antimycobacterial activity. Moreover, both nuclear factor κB (NF-κB) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways were involved in iNOS expression and NO production in inflammatory microenvironment. Furthermore, pro-inflammatory cytokine interleukin-1β could trigger NO production in MSCs and exert anti-mycobacterial activity via NF-κB signaling pathway. Neutralization of interleukin-1β in macrophage-mediated inflammatory microenvironment dampened the ability of mouse MSCs to produce NO. Together, our findings demonstrated that macrophage-mediated inflammatory response during mycobacterial infection promotes the clearance of bacilli in mouse MSCs by increasing NO production, which may provide a better understanding of latent MTB infection. PMID:27251437

  15. Test of the antiorthostatic suspension model on mice - Effects on the inflammatory cell response

    NASA Technical Reports Server (NTRS)

    Rosenkrans, Charles F., Jr.; Chapes, Stephen K.; Fleming, Sherry D.

    1990-01-01

    The antiorthostatic suspension model was tested for use as a 1G model to study the effects of factors that will be encountered during space travel on inflammation. No differences were found in inflammatory cells induced in antiorthostatically suspended mice. However, the superoxide response (used for oxidative killing of bacteria such as S. aureus) was impaired in antiorthostatically oriented mice compared to control mice. Elevated corticosterone levels were found in antiorthostatically suspended mice, indicating that stress may be a factor in the model. If the stress factor of the model correlates with the physiological stress of space flight, antiorthostatic suspension may be an acceptable model for studying inflammatory responses in mice.

  16. The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia.

    PubMed

    Ponnazhagan, Ranjani; Harms, Ashley S; Thome, Aaron D; Jurkuvenaite, Asta; Gogliotti, Rocco; Niswender, Colleen M; Conn, P Jeffrey; Standaert, David G

    2016-06-01

    While the specific trigger of Parkinson Disease (PD) in most patients is unknown, considerable evidence suggests that the neuroinflammatory response makes an essential contribution to the neurodegenerative process. Drugs targeting metabotropic glutamate receptors (mGlu receptors), 7 Transmembrane (7TM) spanning/G protein coupled receptors that bind glutamate, are emerging as therapeutic targets for PD and may have anti-inflammatory properties. ADX88178 is novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 which is under evaluation for treatment of PD and other neurological disorders. We used microglia cultured from mouse brain to determine if ADX88178 had direct effects on the inflammatory responses of these cells. We studied both microglia from wild type and Grm4 knock out mice. We found that activation of mGlu4 with ADX88178 attenuated LPS-induced inflammation in primary microglia, leading to a decrease in the expression of TNFα, MHCII, and iNOS, markers of pro-inflammatory responses. These effects were absent in microglia from mice lacking mGlu4. These results demonstrate a cell-autonomous anti-inflammatory effect of ADX88178 mediated mGlu4 activation on microglia, and suggest that this drug or similar activators or potentiators of mGlu4 may have disease-modifying as well as symptomatic effects in PD and other brain disorders with an inflammatory component. PMID:26872456

  17. Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage.

    PubMed

    Askenase, Michael H; Sansing, Lauren H

    2016-06-01

    Intracerebral hemorrhage (ICH) is a major health concern, with high rates of mortality and morbidity and no highly effective clinical interventions. Basic research in animal models of ICH has provided insight into its complex pathology, in particular revealing the role of inflammation in driving neuronal death and neurologic deficits after hemorrhage. The response to ICH occurs in four distinct phases: (1) initial tissue damage and local activation of inflammatory factors, (2) inflammation-driven breakdown of the blood-brain barrier, (3) recruitment of circulating inflammatory cells and subsequent secondary immunopathology, and (4) engagement of tissue repair responses that promote tissue repair and restoration of neurologic function. The development of CNS inflammation occurs over many days after initial hemorrhage and thus may represent an ideal target for treatment of the disease, but further research is required to identify the mechanisms that promote engagement of inflammatory versus anti-inflammatory pathways. In this review, the authors examine how experimental models of ICH have uncovered critical mediators of pathology in each of the four stages of the inflammatory response, and focus on the role of the immune system in these processes. PMID:27214704

  18. Reduced stress and inflammatory responsiveness in experienced meditators compared to a matched healthy control group.

    PubMed

    Rosenkranz, Melissa A; Lutz, Antoine; Perlman, David M; Bachhuber, David R W; Schuyler, Brianna S; MacCoon, Donal G; Davidson, Richard J

    2016-06-01

    Psychological stress is a major contributor to symptom exacerbation across many chronic inflammatory conditions and can acutely provoke increases in inflammation in healthy individuals. With the rise in rates of inflammation-related medical conditions, evidence for behavioral approaches that reduce stress reactivity is of value. Here, we compare 31 experienced meditators, with an average of approximately 9000 lifetime hours of meditation practice (M age=51years) to an age- and sex-matched control group (n=37; M age=48years) on measures of stress- and inflammatory responsivity, and measures of psychological health. The Trier Social Stress Test (TSST) was used to induce psychological stress and a neurogenic inflammatory response was produced using topical application of capsaicin cream to forearm skin. Size of the capsaicin-induced flare response and increase in salivary cortisol and alpha amylase were used to quantify the magnitude of inflammatory and stress responses, respectively. Results show that experienced meditators have lower TSST-evoked cortisol (62.62±2.52 vs. 70.38±2.33; p<.05) and perceived stress (4.18±.41 vs. 5.56±.30; p<.01), as well as a smaller neurogenic inflammatory response (81.55±4.6 vs. 96.76±4.26; p<.05), compared to the control group. Moreover, experienced meditators reported higher levels of psychological factors associated with wellbeing and resilience. These results suggest that the long-term practice of meditation may reduce stress reactivity and could be of therapeutic benefit in chronic inflammatory conditions characterized by neurogenic inflammation. PMID:26970711

  19. dl-2-Hydroxyisocaproic Acid Attenuates Inflammatory Responses in a Murine Candida albicans Biofilm Model

    PubMed Central

    Nieminen, M. T.; Hernandez, M.; Novak-Frazer, L.; Kuula, H.; Ramage, G.; Bowyer, P.; Warn, P.; Sorsa, T.

    2014-01-01

    Chronic biofilm infections are often accompanied by a chronic inflammatory response, leading to impaired healing and increased, irreversible damage to host tissues. Biofilm formation is a major virulence factor for Candida albicans and a challenge for treatment. Most current antifungals have proved ineffective in eradicating infections attributed to biofilms. The biofilm structure protects Candida species against antifungals and provides a way for them to evade host immune systems. This leads to a very distinct inflammatory response compared to that seen in planktonic infections. Previously, we showed the superior efficacy of dl-2-hydroxyisocaproic acid (HICA) against various bacteria and fungi. However, the immunomodulatory properties of HICA have not been studied. Our aim was to investigate the potential anti-inflammatory response to HICA in vivo. We hypothesized that HICA reduces the levels of immune mediators and attenuates the inflammatory response. In a murine model, a robust biofilm was formed for 5 days in a diffusion chamber implanted underneath mouse skin. The biofilm was treated for 12 h with HICA, while caspofungin and phosphate-buffered saline (PBS) were used as controls. The pathophysiology and immunoexpression in the tissues surrounding the chamber were determined by immunohistochemistry. Histopathological examination showed an attenuated inflammatory response together with reduced expression of matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) compared to those of chambers containing caspofungin and PBS. Interestingly, the expression of developmental endothelial locus 1 (Del-1), an antagonist of neutrophil extravasation, increased after treatment with HICA. Considering its anti-inflammatory and antimicrobial activity, HICA may have enormous therapeutic potential in the treatment of chronic biofilm infections and inflammation, such as those seen with chronic wounds. PMID:24990903

  20. Recombinant thrombomodulin inhibits lipopolysaccharide-induced inflammatory response by blocking the functions of CD14.

    PubMed

    Ma, Chih-Yuan; Chang, Wei-En; Shi, Guey-Yueh; Chang, Bi-Ying; Cheng, Sheng-En; Shih, Yun-Tai; Wu, Hua-Lin

    2015-02-15

    CD14, a multiligand pattern-recognition receptor, is involved in the activation of many TLRs. Thrombomodulin (TM), a type I transmembrane glycoprotein, originally was identified as an anticoagulant factor that activates protein C. Previously, we showed that the recombinant TM lectin-like domain binds to LPS and inhibits LPS-induced inflammation, but the function of the recombinant epidermal growth factor-like domain plus serine/threonine-rich domain of TM (rTMD23) in LPS-induced inflammation remains unknown. In the current study, we found that rTMD23 markedly suppressed the activation of intracellular signaling pathways and the production of inflammatory cytokines induced by LPS. The anti-inflammatory activity of rTMD23 was independent of activated protein C. We also found that rTMD23 interacted with the soluble and membrane forms of CD14 and inhibited the CD14-mediated inflammatory response. Knockdown of CD14 in macrophages suppressed the production of inflammatory cytokines induced by LPS, and rTMD23 inhibited LPS-induced IL-6 production in CD14-knockdown macrophages. rTMD23 suppressed the binding of LPS to macrophages by blocking the association between monocytic membrane-bound TM and CD14. The administration of rTMD23 in mice, both pretreatment and posttreatment, significantly increased the survival rate and reduced the inflammatory response to LPS. Notably, the serine/threonine-rich domain is essential for the anti-inflammatory activity of rTMD23. To summarize, we show that rTMD23 suppresses the LPS-induced inflammatory response in mice by targeting CD14 and that the serine/threonine-rich domain is crucial for the inhibitory effect of rTMD23 on LPS-induced inflammation. PMID:25609841

  1. Interaction of inflammatory and anti-inflammatory responses in microglia by Staphylococcus aureus-derived lipoteichoic acid

    SciTech Connect

    Huang, Bor-Ren; Tsai, Cheng-Fang; Lin, Hsiao-Yun; Tseng, Wen-Pei; Huang, Shiang-Suo; Wu, Chi-Rei; Lin, Chingju; Yeh, Wei-Lan; Lu, Dah-Yuu

    2013-05-15

    We investigated the interaction between proinflammatory and inflammatory responses caused by Staphylococcus aureus-derived lipoteichoic acid (LTA) in primary cultured microglial cells and BV-2 microglia. LTA induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels increase in a concentration- and time-dependent manner. Meanwhile, LTA also increased nitric oxide (NO) and PGE{sub 2} production in microglia. Administration of TLR2 antagonist effectively inhibited LTA-induced NO, iNOS, and COX-2 expression. Moreover, treatment of cells with LTA caused a time-dependent activation of ERK, p38, JNK, as well as AKT. We also found that LTA-induced iNOS and COX-2 up-regulation were attenuated by p38, JNK, and PI3-kinase inhibitors. On the other hand, LTA-enhanced HO-1 expression was attenuated by p38 and PI3-kinase inhibitors. Treatment of cells with NF-κB and AP-1 inhibitors antagonized LTA-induced iNOS and COX-2 expression. However, only NF-κB inhibitors reduced LTA-induced HO-1 expression in microglia. Furthermore, stimulation of cells with LTA also activated IκBα phosphorylation, p65 phosphorylation at Ser{sup 536}, and c-Jun phosphorylation. Moreover, LTA-induced increases of κB-DNA and AP-1-DNA binding activity were inhibited by p38, JNK, and PI3-kinase inhibitors. HO-1 activator CoPP IX dramatically reversed LTA-induced iNOS expression. Our results provided mechanisms linking LTA and inflammation/anti-inflammation, and indicated that LTA plays a regulatory role in microglia activation. - Highlights: • LTA causes an increase in iNOS, COX-2, and HO-1 expression in microglia. • LTA induces iNOS and COX-2 expression through TLR-2/NF-κB and AP-1 pathways. • HO-1 expression is regulated through p38, JNK, PI3K/AKT and AP-1 pathways. • Induced HO-1 reduces LTA-induced iNOS expression. • LTA plays a regulatory role on inflammatory/anti-inflammatory responses.

  2. Maternal Microbe-Specific Modulation of Inflammatory Response in Extremely Low-Gestational-Age Newborns

    PubMed Central

    Fichorova, Raina N.; Onderdonk, Andrew B.; Yamamoto, Hidemi; Delaney, Mary L.; DuBois, Andrea M.; Allred, Elizabeth; Leviton, Alan

    2011-01-01

    The fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins. Lactobacillus was associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and that Lactobacillus may suppress these responses. PMID:21264056

  3. A murine model of stress controllability attenuates Th2-dominant airway inflammatory responses

    PubMed Central

    Deshmukh, Aniket; Kim, Byung-Jin; Gonzales, Xavier; Caffrey, James; Vishwanatha, Jamboor; Jones, Harlan P.

    2010-01-01

    Epidemiological and experimental studies suggest a positive correlation between chronic respiratory inflammatory disease and the ability to cope with adverse stress. Interactions between neuroendocrine and immune systems are believed to provide insight toward the biological mechanisms of action. The utility of an experimental murine model was employed to investigate the immunological consequences of stress-controllability and ovalbumin-induced airway inflammation. Pre-conditioned uncontrollable stress exacerbated OVA-induced lung histopathological changes that were typical of Th2-predominant inflammatory response along respiratory tissues. Importantly, mice given the ability to exert control over aversive stress attenuated inflammatory responses and reduced lung pathology. This model represents a means of investigating the neuro-immune axis in defining mechanisms of stress and respiratory disease. PMID:20462642

  4. Suppression of LPS-induced inflammatory responses by inflexanin B in BV2 microglial cells.

    PubMed

    Lim, Ji-Youn; Sul, Donggeun; Hwang, Bang Yeon; Hwang, Kwang Woo; Yoo, Ki-Yeol; Park, So-Young

    2013-02-01

    Microglia are a type of resident macrophage that functions as an inflammation modulator in the central nervous system. Over-activation of microglia by a range of stimuli disrupts the physiological homeostasis of the brain, and induces inflammatory response and degenerative processes, such as those implicated in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, we investigated the possible anti-inflammatory mechanisms of inflexanin B in murine microglial BV2 cells. Lipopolysaccharide (LPS) activated BV2 cells and induced the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines (interleukins-1β and -6, and tumour necrosis factor α). The LPS-induced production of pro-inflammatory mediators was associated with the enhancement of nuclear factor-kappaB (NF-κB) nuclear translocation and the activation of mitogen-activated protein kinase (MAPK) including ERK1/2 and JNK. Conversely, pretreatment of cells with inflexanin B (10 and 20 μg/mL) significantly reduced the production of pro-inflammatory mediators. This was accompanied with the reduced nuclear translocation of NF-κB and reduced activation of MAPKs. These results suggest that inflexanin B attenuated the LPS-induced inflammatory process by inhibiting the activation of NF-κB and MAPKs. PMID:23458198

  5. A novel interleukin 33/ST2 signaling regulates inflammatory response in human corneal epithelium.

    PubMed

    Lin, Jing; Zhang, Lili; Zhao, Guiqiu; Su, Zhitao; Deng, Ruzhi; Pflugfelder, Stephen C; Li, De-Quan

    2013-01-01

    Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediators. This study was to identify the presence and function of ST2 and explore the role of IL-33/ST2 signaling in regulating the inflammatory cytokine production in corneal epithelial cells. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokine and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 mRNA and protein were detected in donor corneal epithelium and cultured HCECs, and ST2 signal was enhanced by exposure to IL-33. IL-33 significantly stimulated the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein phosphorylation and nuclear translocation, and also suppressed the production of these inflammatory cytokines and chemokine induced by IL-33. These findings demonstrate that ST2 is present in human corneal epithelial cells, and IL-33/ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses in ocular surface. PMID:23585867

  6. A Novel Interleukin 33/ST2 Signaling Regulates Inflammatory Response in Human Corneal Epithelium

    PubMed Central

    Lin, Jing; Zhang, Lili; Zhao, Guiqiu; Su, Zhitao; Deng, Ruzhi; Pflugfelder, Stephen C.; Li, De-Quan

    2013-01-01

    Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediators. This study was to identify the presence and function of ST2 and explore the role of IL-33/ST2 signaling in regulating the inflammatory cytokine production in corneal epithelial cells. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokine and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 mRNA and protein were detected in donor corneal epithelium and cultured HCECs, and ST2 signal was enhanced by exposure to IL-33. IL-33 significantly stimulated the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein phosphorylation and nuclear translocation, and also suppressed the production of these inflammatory cytokines and chemokine induced by IL-33. These findings demonstrate that ST2 is present in human corneal epithelial cells, and IL-33/ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses in ocular surface. PMID:23585867

  7. Magnesium lithospermate B reduces inflammatory response in a mouse model of hepatic ischemia-reperfusion injury.

    PubMed

    Song, Shaohua; Liu, Wenyu; Liu, Fang; Wang, Zhengxin; Ding, Guoshan; Guo, Wenyuan; Fu, Zhiren

    2014-06-01

    It has been well proved that acute inflammatory response and hepatocellular apoptosis contributed to the pathogenesis of liver ischemia reperfusion (IR) injury. A vast amount of research has demonstrated that magnesium lithospermate B (MLB) has potent anti-apoptosis and potential anti-inflammatory pharmacological properties. However, it has not previously been examined whether MLB can attenuate hepatic IR injury. Firstly, the optimal dose of MLB to protect against hepatic IR injury was determined using hepatic IR model in mice. Then, the effect of MLB on IR-induced inflammatory response was detected in detail. We found that MLB exhibited protective effect from the beginning of 50 mg/kg and culminated at the doses of 100 and 200 mg/kg. The alanine aminotransferase and aspartate aminotransferase levels in MLB group were markedly decreased. Severe hepatocellular swelling/necrosis, sinusoidal/vascular congestion and inflammatory cell infiltration were seen and a large number of apoptotic cells were found in the liver samples from Saline group, while minimal damage and very few apoptotic cells were noted in the samples from MLB group. Kuppfer cells infiltration, myeloperoxidase activity and mRNA level of CD11b in MLB group was significantly decreased. Serum TNF-a and IL-6, and mRNA expression of CXCL-10 and ICAM-1 was markedly decreased in the samples from MLB group. Inflammatory signaling pathway activation was largely prevented in MLB group. MLB can significantly attenuate IR-induced hepatocellular damage and hepatocellular apoptosis by preventing inflammatory signaling pathways activation, inflammatory mediators expression and macrophage and neutrophil infiltration. PMID:24385154

  8. microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease.

    PubMed

    Thome, Aaron D; Harms, Ashley S; Volpicelli-Daley, Laura A; Standaert, David G

    2016-02-24

    Increasing evidence points to inflammation as a chief mediator of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein α-synuclein (α-syn). Recently, microRNAs, small, noncoding RNAs involved in regulating gene expression at the posttranscriptional level, have been recognized as important regulators of the inflammatory environment. Using an array approach, we found significant upregulation of microRNA-155 (miR-155) in an in vivo model of PD produced by adeno-associated-virus-mediated expression of α-syn. Using a mouse with a complete deletion of miR-155, we found that loss of miR-155 reduced proinflammatory responses to α-syn and blocked α-syn-induced neurodegeneration. In primary microglia from miR-155(-/-) mice, we observed a markedly reduced inflammatory response to α-syn fibrils, with attenuation of major histocompatibility complex class II (MHCII) and proinflammatory inducible nitric oxide synthase expression. Treatment of these microglia with a synthetic mimic of miR-155 restored the inflammatory response to α-syn fibrils. Our results suggest that miR-155 has a central role in the inflammatory response to α-syn in the brain and in α-syn-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to α-syn. These data implicate miR-155 as a potential therapeutic target for regulating the inflammatory response in PD. PMID:26911687

  9. Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases.

    PubMed

    Woo, Joo Hong; Lee, Jee Hoon; Kim, Hyunmi; Park, Soo Jung; Joe, Eun-Hye; Jou, Ilo

    2015-06-01

    The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses. In this review, we describe the endogenous inflammatory stimulators and signaling pathways in the brain. In particular, our group has focused on the JAK-STAT pathway, identifying anti-inflammatory targets and testing the effects of various anti-inflammatory drugs. This work has shown that the JAK-STAT pathway and its downstream are negatively regulated by phosphatases (SHP2 and MKP-1), inhibitory proteins (SOCS1 and SOCS3) and a nuclear receptor (LXR). These negative regulators are controlled at various levels (e.g. transcriptional, post-transcriptional and post-translational). Future study of these proteins could facilitate the manipulation of the inflammatory response, which plays ubiquitous, diverse and ambivalent roles under physiological and pathological conditions. PMID:26113788

  10. A tetramethoxychalcone from Chloranthus henryi suppresses lipopolysaccharide-induced inflammatory responses in BV2 microglia.

    PubMed

    Luo, Xiao-Ling; Liu, Si-Yu; Wang, Li-Jun; Zhang, Qiu-Yan; Xu, Peng; Pan, Li-Long; Hu, Jin-Feng

    2016-03-01

    Neuroinflammation underlies the pathogenesis and progression of neurodegenerative diseases. 2׳-hydroxy-4,3׳,4׳,6׳-tetramethoxychalcone (HTMC) is a known chalcone derivative isolated from Chloranthus henryi with anti-inflammatory activities in BV2 macrophages. However, its pharmacological effects on microglial cells have not been demonstrated. To this end, we examined the effects of HTMC on lipopolysaccharide (LPS)-induced inflammatory responses in BV2 microglial cells. HTMC concentration-dependently inhibited LPS-induced expression of inflammatory enzymes including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), nitric oxide (NO) production, and the secretion of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. In addition, HTMC inhibited reactive oxygen species (ROS) production by reducing NADPH oxidase (Nox) 2 and Nox4 expression. In addition, HTMC interfered LPS-induced c-Jun N-terminal kinase 1/2 (JNK) phosphorylation in a time- and concentration-dependent manner. By inhibiting phosphorylation and nuclear translocation of Jun, HTMC suppressed LPS-induced activator protein-1 (AP-1) activation. Taken together, our data indicate that HTMC suppresses inflammatory responses in LPS-stimulated BV2 microglial cells by modulating JNK-AP-1 and NADPH oxidases-ROS pathways. HTMC represents a promising therapeutic agent for neurodegenerative and related aging-associated diseases. PMID:26852953

  11. Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide.

    PubMed

    Fonken, Laura K; Weil, Zachary M; Nelson, Randy J

    2013-11-01

    The mammalian circadian system regulates many physiological functions including inflammatory responses. Appropriately timed light information is essential for maintaining circadian organization. Over the past ∼120 years, urbanization and the widespread adoption of electric lights have dramatically altered lighting environments. Exposure to light at night (LAN) is pervasive in modern society and disrupts core circadian clock mechanisms. Because microglia are the resident macrophages in the brain and macrophages contain intrinsic circadian clocks, we hypothesized that chronic exposure to LAN would alter microglia cytokine expression and sickness behavior following LPS administration. Exposure to 4 weeks of dim LAN elevated inflammatory responses in mice. Mice exposed to dimly lit, as compared to dark, nights exaggerated changes in body temperature and elevated microglia pro-inflammatory cytokine expression following LPS administration. Furthermore, dLAN mice had a prolonged sickness response following the LPS challenge. Mice exposed to dark or dimly lit nights had comparable sickness behavior directly following the LPS injection; however, dLAN mice showed greater reductions in locomotor activity, increased anorectic behavior, and increased weight loss than mice maintained in dark nights 24h post-LPS injection. Overall, these data suggest that chronic exposure to even very low levels of light pollution may alter inflammatory responses. These results may have important implications for humans and other urban dwelling species that commonly experience nighttime light exposure. PMID:24012645

  12. Dietary L-arginine supplementation attenuates lipopolysaccharide-induced inflammatory response in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two experiments were conducted to investigate the effect of dietary L-arginine (Arg) supplementation on inflammatory response and innate immunity of broilers. Experiment 1 was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatment; 6 birds/cage) with 3 dietary Arg concentrations (1.05, 1.4...

  13. Dietary L-arginine supplementation modulates lipopolysaccharide-induced systemic inflammatory response in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was conducted to evaluate whether dietary supplementation with L-arginine (Arg) could attenuate lipopolysaccharide (LPS)-induced systemic inflammatory response through LPS/TLR-4 signaling pathway in broilers. The experiment was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatm...

  14. Progressive loss of nigrostriatal dopaminergic neurons induced by inflammatory responses to fipronil.

    PubMed

    Park, Jae Hyeon; Park, Youn Sun; Koh, Hyun Chul

    2016-09-01

    Inflammatory responses are involved in mechanisms of neuronal cell damage in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We investigated the mechanisms whereby inflammatory responses contribute to loss of dopaminergic neurons in fipronil (FPN)-treated rats. After stereotaxic injection of FPN in the substantia nigra (SN), the number of tyrosine hydroxylase (TH)-positive neurons and the levels of TH expression in the SN decreased at 7days, and a significant decrease was observed at 14days with a subsequent reduction in striatal TH expression. Decreases in dopamine (DA) levels, however, began at 3days post-injection, preceding the changes in TH expression. In contrast, glial fibrillary acidic protein (GFAP) expression was significantly increased at 3days and persisted for up to 14days post-lesion; these changes in GFAP expression appeared to be inversely correlated with TH expression. Furthermore, we found that FPN administration induced an inflammatory response characterized by increased levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), which was mediated by activated microglia following infusion of FPN unilaterally into the SN. Intranigral injection of FPN underwent an inflammatory response with a resultant ongoing loss of dopaminergic neurons, indicating that pesticides may have important implication for the study of PD. PMID:27313094

  15. Age-associated changes in immune and inflammatory response: role of nutritional intervention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is associated with dysregulated immune and inflammatory responses. Declined T cell function is best characterized in immuno-senescence. Both intrinsic changes within T cells and extrinsic factors contribute to the age-associated decline in T cell function. T cell defect involves multiple stage...

  16. Differential Pro-Inflammatory Responses of Astrocytes and Microglia Involve STAT3 Activation in Response to 1800 MHz Radiofrequency Fields

    PubMed Central

    Lu, Yonghui; He, Mindi; Zhang, Yang; Xu, Shangcheng; Zhang, Lei; He, Yue; Chen, Chunhai; Liu, Chuan; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

    2014-01-01

    Microglia and astrocytes play important role in maintaining the homeostasis of central nervous system (CNS). Several CNS impacts have been postulated to be associated with radiofrequency (RF) electromagnetic fields exposure. Given the important role of inflammation in neural physiopathologic processes, we investigated the pro-inflammatory responses of microglia and astrocytes and the involved mechanism in response to RF fields. Microglial N9 and astroglial C8-D1A cells were exposed to 1800 MHz RF for different time with or without pretreatment with STAT3 inhibitor. Microglia and astrocytes were activated by RF exposure indicated by up-regulated CD11b and glial fibrillary acidic protein (GFAP). However, RF exposure induced differential pro-inflammatory responses in astrocytes and microglia, characterized by different expression and release profiles of IL-1β, TNF-α, IL-6, PGE2, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Moreover, the RF exposure activated STAT3 in microglia but not in astrocytes. Furthermore, the STAT3 inhibitor Stattic ameliorated the RF-induced release of pro-inflammatory cytokines in microglia but not in astrocytes. Our results demonstrated that RF exposure differentially induced pro-inflammatory responses in microglia and astrocytes, which involved differential activation of STAT3 in microglia and astrocytes. Our data provide novel insights into the potential mechanisms of the reported CNS impacts associated with mobile phone use and present STAT3 as a promising target to protect humans against increasing RF exposure. PMID:25275372

  17. Renal systems biology of patients with systemic inflammatory response syndrome

    PubMed Central

    Tsalik, Ephraim L.; Willig, Laurel K.; Rice, Brandon J.; van Velkinburgh, Jennifer C.; Mohney, Robert P.; McDunn, Jonathan; Dinwiddie, Darrell L.; Miller, Neil A.; Mayer, Eric; Glickman, Seth W.; Jaehne, Anja K.; Glew, Robert H.; Sopori, Mohan L.; Otero, Ronny M.; Harrod, Kevin S.; Cairns, Charles B.; Fowler, Vance G.; Rivers, Emanuel P.; Woods, Christopher W.; Kingsmore, Stephen F.; Langley, Raymond J.

    2015-01-01

    A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular weight proteins and acute phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and n-acetylaspartate were inversely correlated with the majority of significantly down-regulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness. PMID:25993322

  18. Renal systems biology of patients with systemic inflammatory response syndrome.

    PubMed

    Tsalik, Ephraim L; Willig, Laurel K; Rice, Brandon J; van Velkinburgh, Jennifer C; Mohney, Robert P; McDunn, Jonathan E; Dinwiddie, Darrell L; Miller, Neil A; Mayer, Eric S; Glickman, Seth W; Jaehne, Anja K; Glew, Robert H; Sopori, Mohan L; Otero, Ronny M; Harrod, Kevin S; Cairns, Charles B; Fowler, Vance G; Rivers, Emanuel P; Woods, Christopher W; Kingsmore, Stephen F; Langley, Raymond J

    2015-10-01

    A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness. PMID:25993322

  19. HSPA12B inhibits lipopolysaccharide-induced inflammatory response in human umbilical vein endothelial cells

    PubMed Central

    Wu, Jun; Li, Xuehan; Huang, Lei; Jiang, Surong; Tu, Fei; Zhang, Xiaojin; Ma, He; Li, Rongrong; Li, Chuanfu; Li, Yuehua; Ding, Zhengnian; Liu, Li

    2015-01-01

    Heat shock protein A12B (HSPA12B) is a newly discovered member of the HSP70 protein family. This study investigated the effects of HSPA12B on lipopolysaccharide (LPS)-induced inflammatory responses in human umbilical vein endothelial cells (HUVECs) and the possible mechanisms involved. A HUVECs inflammatory model was induced by LPS. Overexpression of HSPA12B in HUVECs was achieved by infection with recombinant adenoviruses encoding green fluorescence protein-HSPA12B. Knockdown of HSPA12B was achieved by siRNA technique. Twenty four hours after virus infection or siRNA transfection, HUVECs were stimulated with 1 μg/ml LPS for 4 hrs. Endothelial cell permeability ability was determined by transwell permeability assay. The binding rate of human neutrophilic polymorphonuclear leucocytes (PMN) with HUVECs was examined using myeloperoxidase assay. Cell migrating ability was determined by the wound-healing assay. The mRNA and protein expression levels of interested genes were analyzed by RT-qPCR and Western blot, respectively. The release of cytokines interleukin-6 and tumour necrosis factor-α was measured by ELISA. HSPA12B suppressed LPS-induced HUVEC permeability and reduced PMN adhesion to HUVECs. HSPA12B also inhibited LPS-induced up-regulation of adhesion molecules and inflammatory cytokine expression. By contrast, knockdown of HSPA12B enhanced LPS-induced increases in the expression of adhesion molecules and inflammatory cytokines. Moreover, HSPA12B activated PI3K/Akt signalling pathway and pharmacological inhibition of this pathway by Wortmannin completely abrogated the protection of HSPA12B against inflammatory response in HUVECs. Our results suggest that HSPA12B attenuates LPS-induced inflammatory responses in HUVECs via activation of PI3K/Akt signalling pathway. PMID:25545050

  20. Mitogen-Activated Protein Kinase Phosphatase 2 Regulates the Inflammatory Response in Sepsis▿

    PubMed Central

    Cornell, Timothy T.; Rodenhouse, Paul; Cai, Qing; Sun, Lei; Shanley, Thomas P.

    2010-01-01

    Sepsis results from a dysregulation of the regulatory mechanisms of the pro- and anti-inflammatory response to invading pathogens. The mitogen-activated protein (MAP) kinase cascades are key signal transduction pathways involved in the cellular production of cytokines. The dual-specific phosphatase 1 (DUSP 1), mitogen-activated protein kinase phosphatase-1 (MKP-1), has been shown to be an important negative regulator of the inflammatory response by regulating the p38 and Jun N-terminal protein kinase (JNK) MAP kinase pathways to influence pro- and anti-inflammatory cytokine production. MKP-2, also a dual-specific phosphatase (DUSP 4), is a phosphatase highly homologous with MKP-1 and is known to regulate MAP kinase signaling; however, its role in regulating the inflammatory response is not known. We hypothesized a regulatory role for MKP-2 in the setting of sepsis. Mice lacking the MKP-2 gene had a survival advantage over wild-type mice when challenged with intraperitoneal lipopolysaccharide (LPS) or a polymicrobial infection via cecal ligation and puncture. The MKP-2−/− mice also exhibited decreased serum levels of both pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], IL-6) and anti-inflammatory cytokines (IL-10) following endotoxin challenge. Isolated bone marrow-derived macrophages (BMDMs) from MKP-2−/− mice showed increased phosphorylation of the extracellular signal-regulated kinase (ERK), decreased phosphorylation of JNK and p38, and increased induction of MKP-1 following LPS stimulation. The capacity for cytokine production increased in MKP-2−/− BMDMs following MKP-1 knockdown. These data support a mechanism by which MKP-2 targets ERK deactivation, thereby decreasing MKP-1 and thus removing the negative inhibition of MKP-1 on cytokine production. PMID:20351138

  1. IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients.

    PubMed

    Mendieta, Danelia; De la Cruz-Aguilera, Dora Luz; Barrera-Villalpando, Maria Isabel; Becerril-Villanueva, Enrique; Arreola, Rodrigo; Hernández-Ferreira, Erick; Pérez-Tapia, Sonia Mayra; Pérez-Sánchez, Gilberto; Garcés-Alvarez, María Eugenia; Aguirre-Cruz, Lucinda; Velasco-Velázquez, Marco Antonio; Pavón, Lenin

    2016-01-15

    Fibromyalgia (FM) is a chronic disease that has been linked to inflammatory reactions and changes in the systemic levels of proinflammatory cytokines that modulate responses in the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. We found that concentrations of IL-6 and IL-8 were elevated in FM patients. Both cytokines correlated with clinical scores, suggesting that IL-6 and IL-8 have additive or synergistic effects in perpetuating the chronic pain in FM patients. These findings indicate that IL-6 and IL-8 are two of the most constant inflammatory mediators in FM and that their levels correlate significantly with the severity of symptoms. PMID:26711564

  2. Innate immune sensors stimulate inflammatory and immunosuppressive responses to UVB radiation.

    PubMed

    Gallo, Richard L; Bernard, Jamie J

    2014-06-01

    Almost 40 years from when it was first reported that UVB radiation exposure would modulate immune signaling, the photoimmunology field is still trying to understand the mechanisms by which UVB initiates inflammatory responses and modulates immune recognition. This commentary focuses on the ability of Toll-like receptors (TLRs), specifically TLR4 (Ahmad et al., 2014) and ligands such as damage-associated molecular patterns (DAMPs) released from injured cells to stimulate innate immune signaling and inflammatory cytokine production following UVB irradiation. PMID:24825061

  3. Recurrent inflammatory pseudotumor of the jaw with perineural intracranial invasion demonstrating sustained response to Rituximab.

    PubMed

    Garcia, Bryan A; Tinsley, Sarah; Schellenberger, Thomas; Bobustuc, George C

    2012-12-01

    Corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab, a chimeric anti-CD20 antibody, has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. This is the first report to describe successful treatment with Rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy. PMID:22161155

  4. Molecular Inflammatory Responses Measured in Blood of Patients with Severe Community-Acquired Pneumonia

    PubMed Central

    Fernández-Serrano, Silvia; Dorca, Jordi; Coromines, Mercè; Carratalà, Jordi; Gudiol, Francesc; Manresa, Frederic

    2003-01-01

    In order to analyze the characteristics of the inflammatory response occurring in blood during pneumonia, we studied 38 patients with severe community-acquired pneumonia. Venous and arterial blood samples were collected at study entry and on days 1, 2, 3, 5, and 7 after inclusion. The concentrations of proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines were determined in order to detect differences related to the origin of the sample, the causative organism, the clinical variables, and the final outcome of the episode. Legionella pneumonia infections showed higher concentrations of TNF-α, IL-6, IL-8, and IL-10. After 24 h, plasma IL-6, IL-8, and IL-10 concentrations in pneumococcal episodes increased, whereas in the same time interval, cytokine concentrations in Legionella episodes markedly decreased. The characteristics of the inflammatory response in bacteremic pneumococcal episodes were different from those in nonbacteremic episodes, as indicated by the higher plasma cytokine concentrations in the former group. Finally, our analysis of cytokine concentrations with regard to the outcome—in terms of the need for intensive care unit admittance and/or mechanical ventilation as well as mortality—suggests that there is a direct relationship between the intensity of the inflammatory response measured in blood and the severity of the episode. PMID:12965910

  5. Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype.

    PubMed

    Akk, Antonina; Springer, Luke E; Pham, Christine T N

    2016-01-01

    Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild-type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase in the alveolar space and plasma that peaked on day 2 post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow-derived cells to release cytokines that can amplify the inflammatory cascade. PMID:27617014

  6. Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype

    PubMed Central

    Akk, Antonina; Springer, Luke E.; Pham, Christine T. N.

    2016-01-01

    Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild-type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase in the alveolar space and plasma that peaked on day 2 post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow-derived cells to release cytokines that can amplify the inflammatory cascade.

  7. Apolipoprotein E knockout induced inflammatory responses related to microglia in neonatal mice brain via astrocytes

    PubMed Central

    Liu, Yimei; Xu, Xiaohua; Dou, Hongbo; Hua, Ying; Xu, Jinwen; Hui, Xu

    2015-01-01

    More and more evidences suggestted that ApoE plays an important role in modulating the systemic and central nervous inflammatory responses. However, there is a lack of exacted mechanism of ApoE. In this study, we aimed to investigate whether apolipoprotein E (ApoE) induced inflammatory responses and apoptosis in neonatal mice brain from ApoE deficient (ApoE-/-) and wildtype (WT). Compared to control group, the microglia cell from ApoE-/- mice showed more severe inflammation and cell death such as iNOS and IL-1β. Furthermore, anti-inflammatory such as TGF-β, IL-10 from microglia and astrocytes in ApoE-/- mice were decreased. On the other way, TGF-β from astrocytes can inhibit inflammation factors secretion from microglia. Our findings suggested that the anti- inflammation factor such as IL-10 mainly from microglia and TGF-β mainly from astrocyte is significant decreased after Loss of ApoE function in ApoE-/- mice which induced severe inflammation. Furthrtmore, anti- inflammation factor such as IL-10 and TGF-β Therefore, we conclude that apolipoprotein E knockout induced inflammatory responses related to microglia in neonatal mice brain via astrocytes. PMID:25785051

  8. Post-traumatic inflammatory response: perhaps a succession of phases with a nutritional purpose.

    PubMed

    Aller, Maria-Angeles; Arias, Jorge-Luis; Arias, Jaime

    2004-01-01

    Post-traumatic inflammatory response, whether this be local or systemic, is considered to be the succession of three functional phases called nervous, immune and endocrine, that could have a nutritional significance. In the nervous phase, ischemia-reperfusion, which causes interstitial and cellular edema, is produced. Both types of edema could represent an ancestral mechanism to feed the cells by diffusion. During the immune phase, the tissues are infiltrated by inflammatory cells and bacteria. Then, extracellular digestion, by enzyme release (fermentation), and intracellular digestion by phagocytosis could be associated with a hypothetical trophic capacity for the neighbouring cells. Finally, in the late or endocrine phase nutrition mediated by the blood capillaries is established. In these three successive phases the inflammatory response goes on from an anaerobic metabolism (ischemia) through a metabolism characterized by a defective oxygen use (reperfusion, oxidative burst and heat hyperproduction) to an oxidative metabolism (oxidative phosphorilation) with a correct use of oxygen to produce usable energy. This type of metabolism is characterized by a large production of ATP, which is used to drive specialized multiple cellular processes. Since the nervous, immune and endocrine phases of the inflammatory response go from ischemia to the development of an oxidative metabolism, It is also tempting to speculate on whether the body reproduces the successive stages by which life passes from its origin without oxygen until it develops an effective, although costly, system for the use of oxygen every time we suffer post-traumatic acute inflammation. PMID:15193345

  9. Decoy Receptor 3 Improves Survival in Experimental Sepsis by Suppressing the Inflammatory Response and Lymphocyte Apoptosis

    PubMed Central

    Liang, DongYu; Hou, YanQiang; Lou, XiaoLi; Chen, HongWei

    2015-01-01

    Purpose Unbalanced inflammatory response and lymphocyte apoptosis is associated with high mortality in septic patients. Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an anti-inflammatory and anti-apoptotic factor. Recently, DcR3 expression was found to be increased in septic patients. This study evaluated the therapeutic effect and mechanisms of DcR3 on cecal ligation and puncture (CLP)-induced sepsis in mice. Methods C57BL/6 mice were subjected to CLP-induced polymicrobial sepsis. DcR3 Fc was intravenously injected 30 min before and 6 h after CLP. Bacterial clearance, cytokine production, histology, lymphocyte apoptosis and survival were evaluated. Furthermore, we investigated the systemic effects of DcR3 in in vitro lymphocyte apoptosis regulation. Results Our results demonstrated that DcR3 protein treatments significantly improved survival in septic mice (p <0.05). Treatment with DcR3 protein significantly reduced the inflammatory response and decreased lymphocyte apoptosis in the thymus and spleen. Histopathological findings of the lung and liver showed milder impairment after DcR3 administration. In vitro experiments showed that DcR3 Fc inhibited Fas-FasL mediated lymphocyte apoptosis. Conclusions Treatment with the DcR3 protein protects mice from sepsis by suppressing the inflammatory response and lymphocyte apoptosis. DcR3 protein may be useful in treatment of sepsis. PMID:26121476

  10. Gemfibrozil attenuates the inflammatory response and protects rats from abdominal sepsis

    PubMed Central

    CÁMARA-LEMARROY, CARLOS R.; GUZMAN-DE LA GARZA, FRANCISCO J.; CORDERO-PEREZ, PAULA; IBARRA-HERNANDEZ, JUAN M.; MUÑOZ-ESPINOSA, LINDA E.; FERNANDEZ-GARZA, NANCY E.

    2015-01-01

    Sepsis is a serious condition characterized by an infectious process that induces a severe systemic inflammatory response. In this study, the effects of gemfibrozil (GFZ) on the inflammatory response associated with abdominal sepsis were investigated using a rat model of cecal-ligation and puncture (CLP). Male Wistar rats were randomly divided into three groups: Sham-operated group (sham), where laparotomy was performed, the intestines were manipulated, and the cecum was ligated but not punctured; control group, subjected to CLP; and GFZ group, which received GFZ prior to undergoing CLP. The groups were then subdivided into three different time-points: 2, 4 and 24 h, indicating the time at which blood samples were obtained for analysis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were determined. The LDH, AST and ALT values were significantly elevated following CLP compared with those in the sham group, and GFZ treatment was able to reduce these elevations. GFZ also reduced the sepsis-induced elevations of TNF-α and IL-1. In conclusion, GFZ treatment was able to attenuate the inflammatory response associated with CLP-induced sepsis, by diminishing the release of inflammatory cytokines, thereby reducing tissue injury and oxidative stress. PMID:25667670

  11. The uptake of PLGA micro or nanoparticles by macrophages provokes distinct in vitro inflammatory response.

    PubMed

    Nicolete, Roberto; dos Santos, Daiane F; Faccioli, Lúcia H

    2011-10-01

    Biodegradable micro/nanoparticles generated from PLGA have recently attracted attention due to their clinically proven biocompatibility, especially for immunization purposes. These polymeric particulate delivery systems are able to present antigens and activate both humoral and cellular responses. Many studies have discussed the ideal size of these particles in contributing to the generation of the different types of immune response. However, these studies do not demonstrate the effect of micro or nanoparticles, without any encapsulated bioactive, on phagocytic cells after the uptake process. In this context, the aim of this study was to analyze the in vitro inflammatory behavior of J774 murine macrophages after particles' uptake, since nano/microparticles per se can differently activate phagocytic cells, using or not appropriate receptors, inducing distinct inflammatory responses. An o/w emulsion solvent extraction-evaporation method was chosen to prepare the particles. We determined their diameters, zeta potential and morphology. Fluorescent particles' uptake by J774 murine "macrophage-like" cells was also analyzed. To evaluate the in vitro inflammatory profile of these cells after micro or nanoparticles' uptake, we conducted NF-κB translocation assay by confocal microscopy and also determined the pro-inflammatory cytokines production provoked by the particles. PMID:21621649

  12. The HMGB1 signaling pathway activates the inflammatory response in Schwann cells

    PubMed Central

    Man, Li-li; Liu, Fan; Wang, Ying-jie; Song, Hong-hua; Xu, Hong-bo; Zhu, Zi-wen; Zhang, Qing; Wang, Yong-jun

    2015-01-01

    Schwann cells are not only myelinating cells, but also function as immune cells and express numerous innate pattern recognition receptors, including the Toll-like receptors. Injury to peripheral nerves activates an inflammatory response in Schwann cells. However, it is unclear whether specific endogenous damage-associated molecular pattern molecules are involved in the inflammatory response following nerve injury. In the present study, we demonstrate that a key damage-associated molecular pattern molecule, high mobility group box 1 (HMGB1), is upregulated following rat sciatic nerve axotomy, and we show colocalization of the protein with Schw-ann cells. HMGB1 alone could not enhance expression of Toll-like receptors or the receptor for advanced glycation end products (RAGE), but was able to facilitate migration of Schwann cells. When Schwann cells were treated with HMGB1 together with lipopolysaccharide, the expression levels of Toll-like receptors and RAGE, as well as inflammatory cytokines were upregulated. Our novel findings demonstrate that the HMGB1 pathway activates the inflammatory response in Schwann cells following peripheral nerve injury. PMID:26692874

  13. Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response

    PubMed Central

    Karmarkar, Dipti; Rock, Kenneth L

    2013-01-01

    In the present study, we have found that intestinal flora strongly influence peritoneal neutrophilic inflammatory responses to diverse stimuli, including pathogen-derived particles like zymosan and sterile irritant particles like crystals. When germ-free and flora-deficient (antibiotic-treated) mice are challenged with zymosan intraperitoneally, neutrophils are markedly impaired in their ability to extravasate from blood into the peritoneum. In contrast, in these animals, neutrophils can extravasate in response to an intraperitoneal injection of the chemokine, macrophage inflammatory protein 2. Neutrophil recruitment upon inflammatory challenge requires stimulation by microbiota through a myeloid differentiation primary response gene (88) (MyD88) -dependent pathway. MyD88 signalling is crucial during the development of the immune system but depending upon the ligand it may be dispensable at the time of the actual inflammatory challenge. Furthermore, pre-treatment of flora-deficient mice with a purified MyD88-pathway agonist is sufficient to restore neutrophil migration. In summary, this study provides insight into the role of gut microbiota in influencing acute inflammation at sites outside the gastrointestinal tract. PMID:23909393

  14. Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice.

    PubMed

    Wang, Jinhui; Hu, Shiwei; Jiang, Wei; Song, Wendong; Cai, Lu; Wang, Jingfeng

    2016-02-01

    Nutrition excess-induced inflammation positively contributed to insulin resistance. Fucoidan from sea cucumber can increase glucose translocation in skeletal muscle. However, its effects on inflammation-associated insulin resistance are not understood. We investigated fucoidan from Isostichopus badionotus (Ib-FUC)-alleviated inflammatory response and signaling as well as -improved insulin resistance in the liver of obesity mice. The results showed that Ib-FUC reduced body weight and glucose levels, increased insulin sensitivity, and inhibited serum lipid concentrations. Meanwhile, Hepatic glycogen synthesis was promoted by Ib-FUC via activation of the PI3K/PKB/GSK-3β signaling and regulation of glucose metabolism-related enzymatic activities. Ib-FUC regulated serum inflammatory cytokines and their mRNA expression in the liver. Ib-FUC-induced inactivation of the JNK and IKKβ/NFκB pathways was involved in the activation of insulin signal cascade and inflammatory factor production. These findings suggested that Ib-FUC supplementary-induced alleviation of inflammatory response could be a mechanism responsible for its beneficial effects against hepatic insulin resistance. PMID:26690975

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

    SciTech Connect

    Kim, Sun Ae; Choi, Hyoung Chul

    2012-09-07

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

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

    PubMed Central

    2012-01-01

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

  17. Three diketopiperazines from marine-derived bacteria inhibit LPS-induced endothelial inflammatory responses.

    PubMed

    Kang, Hyejin; Ku, Sae-Kwang; Choi, Hyukjae; Bae, Jong-Sup

    2016-04-15

    Diketopiperazine is a natural products found from bacteria, fungi, marine sponges, gorgonian and red algae. They are cyclic dipeptides possessing relatively simple and rigid structures with chiral nature and various side chains. Endothelial dysfunction is a key pathological feature of many inflammatory diseases, including sepsis. In the present study, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria. The compounds were investigated for their effects against lipopolysaccharide (LPS)-mediated endothelial inflammatory responses in vitro and in vivo. From 1μM, 1-3 inhibited LPS-induced hyperpermeability, adhesion, and migration of leukocytes across a human endothelial cell monolayer and in mice in a dose-dependent manner suggesting that 1-3 may serve as potential scaffolds for the development of therapeutic agents to treat vascular inflammatory disorders. PMID:26988307

  18. Inflammatory response of macrophages cultured with Helicobacter pylori strains was regulated by miR-155.

    PubMed

    Yao, Yongliang; Li, Guangxin; Wu, Jianhong; Zhang, Xian; Wang, Jianjun

    2015-01-01

    MicroRNA-155 plays an important role in the inflammatory response macrophages, while present studies identified that miR-155 was up-expressed in gastritis induced by Helicobacter pylori. We found that miR-155 was over expressed in macrophages infected with H. pylori in vivo or in vitro. Subsequently, inflammatory cytokines IL-23, IL-10, TNF-α and IL-8 were increased significantly, and the expression of CD80, CD86 or COX2, NOS2. Were enhanced in H. pylori infection macrophages by regulated with miR-155mimics. Furthermore, the apoptosis of macrophages induced by H. pylori was increased obviously due to the over-expression of miR-155. Therefore, these observations indicated that miR-155 may act as a inflammatory promoter in H. pylori infected macrophages. These findings contribute us to understand the functions of miR-155 in gastritis induced by H. pylori furtherly. PMID:26191144

  19. Effects of Thymol and Carvacrol, Constituents of Thymus vulgaris L. Essential Oil, on the Inflammatory Response

    PubMed Central

    Fachini-Queiroz, Fernanda Carolina; Kummer, Raquel; Estevão-Silva, Camila Fernanda; Carvalho, Maria Dalva de Barros; Cunha, Joice Maria; Grespan, Renata; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2012-01-01

    Thyme (Thymus vulgaris L., Lamiaceae) is an aromatic and medicinal plant that has been used in folk medicine, phytopharmaceutical preparations, food preservatives, and as an aromatic ingredient. The effect of Thymus vulgaris essential oil (TEO) and its isolated constituents thymol and cavacrol (CVL) were studied in the following experimental models: ear edema, carrageenan-induced pleurisy, and chemotaxis in vitro. In the pleurisy model, TEO, CVL, and thymol significantly inhibited inflammatory edema. However, only TEO and CVL inhibited leukocyte migration. In the in vitro chemotaxis experiment, CVL inhibited leukocyte migration, whereas thymol exerted a potent chemoattractant effect. In the ear edema model, CVL (10 mg/ear), applied topically, reduced edema formation, exerting a topical anti-inflammatory effect. Thymol did not reduce edema formation but rather presented an irritative response, probably dependent on histamine and prostanoid release. Our data suggest that the antiinflammatory effects of TEO and CVL are attributable to the inhibition of inflammatory edema and leukocyte migration. PMID:22919415

  20. Bioinformatics analysis of the early inflammatory response in a rat thermal injury model

    PubMed Central

    Yang, Eric; Maguire, Timothy; Yarmush, Martin L; Berthiaume, Francois; Androulakis, Ioannis P

    2007-01-01

    Background Thermal injury is among the most severe forms of trauma and its effects are both local and systemic. Response to thermal injury includes cellular protection mechanisms, inflammation, hypermetabolism, prolonged catabolism, organ dysfunction and immuno-suppression. It has been hypothesized that gene expression patterns in the liver will change with severe burns, thus reflecting the role the liver plays in the response to burn injury. Characterizing the molecular fingerprint (i.e., expression profile) of the inflammatory response resulting from burns may help elucidate the activated mechanisms and suggest new therapeutic intervention. In this paper we propose a novel integrated framework for analyzing time-series transcriptional data, with emphasis on the burn-induced response within the context of the rat animal model. Our analysis robustly identifies critical expression motifs, indicative of the dynamic evolution of the inflammatory response and we further propose a putative reconstruction of the associated transcription factor activities. Results Implementation of our algorithm on data obtained from an animal (rat) burn injury study identified 281 genes corresponding to 4 unique profiles. Enrichment evaluation upon both gene ontologies and transcription factors, verifies the inflammation-specific character of the selections and the rationalization of the burn-induced inflammatory response. Conducting the transcription network reconstruction and analysis, we have identified transcription factors, including AHR, Octamer Binding Proteins, Kruppel-like Factors, and cell cycle regulators as being highly important to an organism's response to burn response. These transcription factors are notable due to their roles in pathways that play a part in the gross physiological response to burn such as changes in the immune response and inflammation. Conclusion Our results indicate that our novel selection/classification algorithm has been successful in selecting out

  1. Dexamethasone Coated Neural Probes Elicit Attenuated Inflammatory Response and Neuronal Loss Compared to Uncoated Neural Probes

    PubMed Central

    Zhong, Yinghui; Bellamkonda, Ravi V.

    2007-01-01

    Glial scar formation around implanted silicon neural probes compromises their ability to facilitate long-term recordings. One approach to modulate the tissue reaction around implanted probes in the brain is to develop probe coatings that locally release antiinflammatory drugs. In this study, we developed a nitrocellulose-based coating for the local delivery of the anti-inflammatory drug dexamethasone (DEX). Silicon neural probes with and without nitrocellulose-DEX coatings were implanted into rat brains, and inflammatory response was evaluated 1 week and 4 weeks post implantation. DEX coatings significantly reduced the reactivity of microglia and macrophages one week post implantation as evidenced by ED1 immunostaining. CS56 staining demonstrated that DEX treatment significantly reduced chondroitin sulfate proteoglycan (CSPG) expression one week post implantation. Both at one week and at four week time points, GFAP staining for reactive astrocytes and neurofilament (NF) staining revealed that local DEX treatment significantly attenuated astroglial response and reduced neuronal loss in the vicinity of the probes. Weak ED1, neurocan, and NG2 positive signal was detected four weeks post implantation for both coated and uncoated probes, suggesting a stabilization of the inflammatory response over time in this implant model. In conclusion, this study demonstrates that the nitrocellulose-DEX coating can effectively attenuate the inflammatory response to the implanted neural probes, and reduce neuronal loss in the vicinity of the coated probes. Thus anti-inflammatory probe coatings may represent a promising approach to attenuate astroglial scar and reduce neural loss around implanted neural probes. PMID:17376408

  2. OXYGEN MITIGATES THE INFLAMMATORY RESPONSE IN A MODEL OF HEMORRHAGE AND ZYMOSAN-INDUCED INFLAMMATION.

    PubMed

    Rahat, Michal A; Brod, Vera; Amit-Cohen, Bat-Chen; Henig, Oryan; Younis, Said; Bitterman, Haim

    2016-02-01

    Sequential insults (hits) may change the inflammatory reaction that develops in response to separate single hits (e.g., injury, infection); however, their effects on the long-term clinical outcome are still only partially elucidated. Double-hit models are typically severe and fatal. We characterized in C57BL/6 mice a moderate double-hit model of hemorrhage (35%-40% of total blood volume) and resuscitation, followed by peritoneal injection of zymosan A that induced local and systemic inflammation with 58% mortality. This model allowed exploration of the inflammatory response over time in the surviving mice. We show that after 2 days, mice subjected to the double-hit model had elevated proinflammatory systemic and local peritoneal cytokine response (interleukin [IL]-1β, tumor necrosis factor-α, IL-6) and moderately elevated anti-inflammatory cytokines (IL-10, transforming growth factor-β), compared with the single-hit and sham mice. However, this dynamically changed, and by day 7, proinflammatory cytokines were reduced, and anti-inflammatory cytokines were markedly (P < 0.05) elevated in the double-hit group. Mice in the double-hit group that inhaled 100% oxygen intermittently for 6 h every day exhibited markedly reduced serum proinflammatory cytokines as early as day 2 (P < 0.05), inhibited macrophage infiltration into the peritoneum (by 13-fold; P < 0.05), and substantially increased survival rates of 85% (P = 0.00144). Oxygen mitigates the inflammatory response and exerts a beneficial effect on survival in a double-hit model of hemorrhage and zymosan-induced inflammation. PMID:26771936

  3. Leptospira interrogans induces uterine inflammatory responses and abnormal expression of extracellular matrix proteins in dogs.

    PubMed

    Wang, Wei; Gao, Xuejiao; Guo, Mengyao; Zhang, Wenlong; Song, Xiaojing; Wang, Tiancheng; Zhang, Zecai; Jiang, Haichao; Cao, Yongguo; Zhang, Naisheng

    2014-10-01

    Leptospira interrogans (L. interrogans), a worldwide zoonosis, infect humans and animals. In dogs, four syndromes caused by leptospirosis have been identified: icteric, hemorrhagic, uremic (Stuttgart disease) and reproductive (abortion and premature or weak pups), and also it caused inflammation. Extracellular matrix (ECM) is a complex mixture of matrix molecules that is crucial to the reproduction. Both inflammatory response and ECM are closed relative to reproductive. The aim of this study was to clarify how L. interrogans affected the uterus of dogs, by focusing on the inflammatory responses, and ECM expression in dogs uterine tissue infected by L. interrogans. In the present study, 27 dogs were divided into 3 groups, intrauterine infusion with L. interrogans, to make uterine infection, sterile EMJH, and normal saline as a control, respectively. The uteruses were removed by surgical operation in 10, 20, and 30 days, respectively. The methods of histopathological analysis, ELISA, Western blot and qPCR were used. The results showed that L. interrogans induced significantly inflammatory responses, which were characterized by inflammatory cellular infiltration and high expression levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in uterine tissue of these dogs. Furthermore, L. interrogans strongly down-regulated the expression of ECM (collagens (CL) IV, fibronectins (FN) and laminins (LN)) in mRNA and protein levels. These data indicated that strongly inflammatory responses, and abnormal regulation of ECM might contribute to the proliferation of dogs infected by L. interrogans. PMID:25153777

  4. Technical Approach Determines Inflammatory Response after Surgical and Transcatheter Aortic Valve Replacement

    PubMed Central

    Erdoes, Gabor; Lippuner, Christoph; Kocsis, Istvan; Schiff, Marcel; Stucki, Monika; Carrel, Thierry; Windecker, Stephan; Eberle, Balthasar; Stueber, Frank; Book, Malte

    2015-01-01

    Objective To investigate the periprocedural inflammatory response in patients with isolated aortic valve stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) with different technical approaches. Material and Methods Patients were prospectively allocated to one of the following treatments: SAVR using conventional extracorporeal circulation (CECC, n = 47) or minimized extracorporeal circulation (MECC, n = 15), or TAVI using either transapical (TA, n = 15) or transfemoral (TF, n = 24) access. Exclusion criteria included infection, pre-procedural immunosuppressive or antibiotic drug therapy and emergency indications. We investigated interleukin (IL)-6, IL-8, IL-10, human leukocyte antigen (HLA-DR), white blood cell count, high-sensitivity C-reactive protein (hs-CRP) and soluble L-selectin (sCD62L) levels before the procedure and at 4, 24, and 48 h after aortic valve replacement. Data are presented for group interaction (p-values for inter-group comparison) as determined by the Greenhouse-Geisser correction. Results SAVR on CECC was associated with the highest levels of IL-8 and hs-CRP (p<0.017, and 0.007, respectively). SAVR on MECC showed the highest descent in levels of HLA-DR and sCD62L (both p<0.001) in the perioperative period. TA-TAVI showed increased intraprocedural concentration and the highest peak of IL-6 (p = 0.017). Significantly smaller changes in the inflammatory markers were observed in TF-TAVI. Conclusion Surgical and interventional approaches to aortic valve replacement result in inflammatory modulation which differs according to the invasiveness of the procedure. As expected, extracorporeal circulation is associated with the most marked pro-inflammatory activation, whereas TF-TAVI emerges as the approach with the most attenuated inflammatory response. Factors such as the pre-treatment patient condition and the extent of myocardial injury also significantly affect inflammatory biomarker patterns

  5. EGCG Attenuates Uric Acid-Induced Inflammatory and Oxidative Stress Responses by Medicating the NOTCH Pathway

    PubMed Central

    Xie, Hua; Sun, Jianqin; Chen, Yanqiu; Zong, Min; Li, Shijie; Wang, Yan

    2015-01-01

    Background. The aim of this study is to investigate whether (-)-epigallocatechin-3-gallate (EGCG) can prevent the UA-induced inflammatory effect of human umbilical vein endothelial cells (HUVEC) and the involved mechanisms in vitro. Methods. HUVEC were subjected to uric acid (UA) with or without EGCG treatment. RT-PCR and western blots were performed to determine the level of inflammation marker. The antioxidant activity was evaluated by measuring scavenged reactive oxygen species (ROS). Functional studies of the role of Notch-1 in HUVEC lines were performed using RNA interference analyses. Results. UA significantly increased the expressions of IL-6, ICAM-1, TNF-α, and MCP-1 and the production of ROS in HUVEC. Meanwhile, the expression of Notch-1 and its downstream effects significantly increased. Using siRNA, inhibition of Notch-1 signaling significantly impeded the expressions of inflammatory cytokines under UA treatment. Interestingly, EGCG suppressed the expressions of inflammatory cytokines and the generation of ROS. Western blot analysis of Notch-1 showed that EGCG significantly decreased the expressions of inflammatory cytokines through Notch-1 signaling pathways. Conclusions. In summary, our findings indicated that Notch-1 plays an important role in the UA-induced inflammatory response, and the downregulation of Notch-1 by EGCG could be an effective approach to decrease inflammation and oxidative stress induced by UA. PMID:26539255

  6. Safflower Yellow regulates microglial polarization and inhibits inflammatory response in LPS-stimulated Bv2 cells.

    PubMed

    Yang, Xing-Wang; Li, Yan-Hua; Zhang, Hui; Zhao, Yong-Fei; Ding, Zhi-Bin; Yu, Jie-Zhong; Liu, Chun-Yun; Liu, Jian-Chun; Jiang, Wei-Jia; Feng, Qian-Jin; Xiao, Bao-Guo; Ma, Cun-Gen

    2016-03-01

    Activated microglia, especially polarized M1 cells, produce pro-inflammatory cytokines and free radicals, thereby contributing directly to neuroinflammation and various brain disorders. Given that excessive or chronic neuroinflammation within the central nervous system (CNS) exacerbates neuronal damage, molecules that modulate neuroinflammation are candidates as neuroprotective agents. In this study, we provide evidence that Safflor yellow (SY), the main active component in the traditional Chinese medicine safflower, modulates inflammatory responses by acting directly on BV2 microglia. LPS stimulated BV2 cells to upregulate expression of TLR4-Myd88 and MAPK-NF-κB signaling pathways and to release IL-1β, IL-6, TNF-α, and COX-2. However, SY treatment inhibited expression of TLR4-Myd88 and p-38/p-JNK-NF-κB, downregulated expression of iNOS, CD16/32, and IL-12, and upregulated CD206 and IL-10. In conclusion, our results demonstrate that SY exerts an anti-inflammatory effect on BV2 microglia, possibly through TLR-4/p-38/p-JNK/NF-κB signaling pathways and the conversion of microglia from inflammatory M1 to an anti-inflammatory M2 phenotype. PMID:26634402

  7. GBA2-Encoded β-Glucosidase Activity Is Involved in the Inflammatory Response to Pseudomonas aeruginosa

    PubMed Central

    Lampronti, Ilaria; Marchetti, Nicola; Aureli, Massimo; Bassi, Rosaria; Giri, Maria Grazia; Bezzerri, Valentino; Lovato, Valentina; Cantù, Cinzia; Munari, Silvia; Cheng, Seng H.; Cavazzini, Alberto; Gambari, Roberto; Sonnino, Sandro; Cabrini, Giulio; Dechecchi, Maria Cristina

    2014-01-01

    Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF) are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs) in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (Genz-529648). In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2. PMID:25141135

  8. Carvacrol Exerts Neuroprotective Effects Via Suppression of the Inflammatory Response in Middle Cerebral Artery Occlusion Rats.

    PubMed

    Li, Zhenlan; Hua, Cong; Pan, Xiaoqiang; Fu, Xijia; Wu, Wei

    2016-08-01

    Increasing evidence demonstrates that inflammation plays an important role in cerebral ischemia. Carvacrol, a monoterpenic phenol, is naturally occurring in various plants belonging to the family Lamiaceae and exerts protective effects in a mice model of focal cerebral ischemia/reperfusion injury by reducing infarct volume and decreasing the expression of cleaved caspase-3. However, the anti-inflammatory mechanisms by which carvacrol protect the brain have yet to be fully elucidated. We investigated the effects of carvacrol on inflammatory reaction and inflammatory mediators in middle cerebral artery occlusion rats. The results of the present study showed that carvacrol inhibited the levels of inflammatory cytokines and myeloperoxidase (MPO) activity, as well as the expression of iNOS and COX-2. It also increased SOD activity and decreased MDA level in ischemic cortical tissues. In addition, carvacrol treatment suppressed the ischemia/reperfusion-induced increase in the protein expression of nuclear NF-kB p65. In conclusion, we have shown that carvacrol inhibits the inflammatory response via inhibition of the NF-kB signaling pathway in a rat model of focal cerebral ischemia. Therefore, carvacrol may be a potential therapeutic agent for the treatment of cerebral ischemia injury. PMID:27324156

  9. Serotonin Receptor 2B Mediates Mechanical Hyperalgesia by Regulating Transient Receptor Potential Vanilloid 1.

    PubMed

    Su, Yeu-Shiuan; Chiu, Yuan-Yi; Lin, Shih-Yuan; Chen, Chih-Cheng; Sun, Wei-Hsin

    2016-05-01

    Serotonin [5-hydroxytryptamine (5-HT)], an inflammatory mediator, contributes to inflammatory pain. The presence of multiple 5-HT subtype receptors on peripheral and central nociceptors complicates the role of 5-HT in pain. Previously, we found that 5-HT2B/2C antagonist could block 5-HT-induced mechanical hyperalgesia. However, the types of neurons or circuits underlying this effect remained unsolved. Here, we demonstrate that the Gq/11-phospholipase Cβ-protein kinase Cε (PKCε) pathway mediated by 5-HT2B is involved in 5-HT-induced mechanical hyperalgesia in mice. Administration of a transient receptor potential vanilloid 1 (TRPV1) antagonist inhibited the 5-HT-induced mechanical hyperalgesia. 5-HT injection enhanced 5-HT- and capsaicin-evoked calcium signals specifically in isolectin B4 (IB4)-negative neurons; signals were inhibited by a 5-HT2B/2C antagonist and PKCε blocker. Thus, 5-HT2B mediates 5-HT-induced mechanical hyperalgesia by regulating TRPV1 function. PMID:26635025

  10. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis.

    PubMed

    Rimessi, Alessandro; Bezzerri, Valentino; Patergnani, Simone; Marchi, Saverio; Cabrini, Giulio; Pinton, Paolo

    2015-01-01

    The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca(2+) uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation. PMID:25648527

  11. Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity.

    PubMed

    Griffin, C; Lanzetta, N; Eter, L; Singer, K

    2016-08-01

    It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses. PMID:27252473

  12. 20 Years On: Is It Time to Redefine the Systemic Inflammatory Response to Cardiothoracic Surgery?

    PubMed Central

    Landis, R. Clive

    2015-01-01

    Abstract: The “systemic inflammatory response” has never been defined from a cardiothoracic surgery perspective, but borrowed its definition from the critical care field at a landmark 1992 definition conference on sepsis. It is unclear why the diagnostic criteria for the Systemic Inflammatory Response Syndrome (SIRS) were adopted in isolation, ignoring other potentially more useful definitions for Severe Septic Shock or Secondary Multiple Organ Dysfunction Syndrome. The 1992 SIRS definition for sepsis has since been updated at a conference in 2001 advocating PIRO (Predisposition, Infection, host Response, Organ dysfunction) as a hypothetical model to better link sepsis with clinical outcome. PIRO is readily adaptable to cardiothoracic surgery and provides the precedent and road map for how to update a definition. The need is obvious since the current definition of SIRS is widely disregarded in heart surgery: a dwindling proportion (14%) of articles on the systemic inflammatory response even mention SIRS and 0% monitored SIRS criteria in the past decade in an evidence-based review of anti-inflammatory interventions. The name “inflammatory response” is also problematic; it is too narrow and might be replaced with host response (the R in PIRO) to better convey the wide spectrum of host defensive pathways activated during heart surgery (i.e., complement, coagulation, fibrinolysis, kinins, cytokines, proteases, hemolysis, oxidative stress). A variant on PIRO could allow these elements of the host Response (R) to be anchored within the context of Premorbid conditions (P) and the inevitable Insult (I) from surgery, to better link risk exposures to Organ dysfunction (O) in heart surgery. The precedent of PIRO suggests the following steps will be required to redefine the systemic inflammatory response: 1) buy-in from the leading societies for cardiothoracic surgery, anesthesia, and perfusion on the need for a re-definition conference, 2) assigning relative risk

  13. Fasciola hepatica Kunitz Type Molecule Decreases Dendritic Cell Activation and Their Ability to Induce Inflammatory Responses

    PubMed Central

    Falcón, Cristian R.; Masih, Diana; Gatti, Gerardo; Sanchez, María Cecilia; Motrán, Claudia C.; Cervi, Laura

    2014-01-01

    The complete repertoire of proteins with immunomodulatory activity in Fasciola hepatica (Fh) has not yet been fully described. Here, we demonstrated that Fh total extract (TE) reduced LPS-induced DC maturation, and the DC ability to induce allogeneic responses. After TE fractionating, a fraction lower than 10 kDa (F<10 kDa) was able to maintain the TE properties to modulate the DC pro- and anti-inflammatory cytokine production induced by LPS. In addition, TE or F<10 kDa treatment decreased the ability of immature DC to stimulate the allogeneic responses and induced a novo allogeneic CD4+CD25+Foxp3+ T cells. In contrast, treatment of DC with T/L or F<10 kDa plus LPS (F<10/L) induced a regulatory IL-27 dependent mechanism that diminished the proliferative and Th1 and Th17 allogeneic responses. Finally, we showed that a Kunitz type molecule (Fh-KTM), present in F<10 kDa, was responsible for suppressing pro-inflammatory cytokine production in LPS-activated DC, by printing tolerogenic features on DC that impaired their ability to induce inflammatory responses. These results suggest a modulatory role for this protein, which may be involved in the immune evasion mechanisms of the parasite. PMID:25486609

  14. Mycobacterium fortuitum induces A20 expression that impairs macrophage inflammatory responses.

    PubMed

    Lee, Gippeum Joy; Lee, Hye-Mi; Kim, Tae Sung; Kim, Jin Kyung; Sohn, Kyung Mok; Jo, Eun-Kyeong

    2016-04-01

    Mycobacterium fortuitum is a rapidly growing mycobacterium that has been regarded as an etiological agent of a variety of human infections. However, little is known about the host inflammatory responses and the molecular mechanisms by which MF-induced inflammation is regulated in macrophages. In this study, we report that MF infection leads to the induction of an anti-inflammatory molecule, A20 (also known as TNFAIP3), which is essential for the regulation of MF-induced inflammatory responses in murine bone marrow-derived macrophages (BMDMs). MF triggered the expression of tumor necrosis factor-α and interleukin-6 in BMDMs through signaling of the Toll-like receptor 2 (TLR2)-myeloid differentiation primary response gene 88. Additionally, MF rapidly induced the expression of A20, which inhibited proinflammatory cytokine expression and nuclear factor (NF)-κB reporter gene activities in BMDMs. Notably, MF-induced activation of NF-κB signaling was required for A20 expression and proinflammatory responses in BMDMs. Furthermore, the rough morphotype of the MF clinical strain induced a higher level of proinflammatory signaling activation, but less A20 induction in BMDMs, compared to the smooth morphotype. Taken together, these results suggest that MF-induced activation of host proinflammatory responses is negatively regulated through TLR2-dependent A20 expression. PMID:26940588

  15. Intensity modulated radiotherapy induces pro-inflammatory and pro-survival responses in prostate cancer patients

    PubMed Central

    EL-SAGHIRE, HOUSSEIN; VANDEVOORDE, CHARLOT; OST, PIET; MONSIEURS, PIETER; MICHAUX, ARLETTE; DE MEERLEER, GERT; BAATOUT, SARAH; THIERENS, HUBERT

    2014-01-01

    Intensity modulated radiotherapy (IMRT) is one of the modern conformal radiotherapies that is widely used within the context of cancer patient treatment. It uses multiple radiation beams targeted to the tumor, however, large volumes of the body receive low doses of irradiation. Using γ-H2AX and global genome expression analysis, we studied the biological responses induced by low doses of ionizing radiation in prostate cancer patients following IMRT. By means of different bioinformatics analyses, we report that IMRT induced an inflammatory response via the induction of viral, adaptive, and innate immune signaling. In response to growth factors and immune-stimulatory signaling, positive regulation in the progression of cell cycle and DNA replication were induced. This denotes pro-inflammatory and pro-survival responses. Furthermore, double strand DNA breaks were induced in every patient 30 min after the treatment and remaining DNA repair and damage signaling continued after 18–24 h. Nine genes belonging to inflammatory responses (TLR3, SH2D1A and IL18), cell cycle progression (ORC4, SMC2 and CCDC99) and DNA damage and repair (RAD17, SMC6 and MRE11A) were confirmed by quantitative RT-PCR. This study emphasizes that the risk assessment of health effects from the out-of-field low doses during IMRT should be of concern, as these may increase the risk of secondary cancers and/or systemic inflammation. PMID:24435511

  16. Potential Use of Salivary Markers for Longitudinal Monitoring of Inflammatory Immune Responses to Vaccination

    PubMed Central

    Garssen, Johan; Sandalova, Elena

    2016-01-01

    Vaccination, designed to trigger a protective immune response against infection, is a trigger for mild inflammatory responses. Vaccination studies can address the question of inflammation initiation, levels, and resolution as well as its regulation for respective studied pathogens. Such studies largely based on analyzing the blood components including specific antibodies and cytokines were usually constrained by number of participants and volume of collected blood sample. Hence, blood-based studies may not be able to cover the full dynamic range of inflammation responses induced by vaccination. In this review, the potential of using saliva in addition to blood for studying the kinetics of inflammatory response studies was assessed. Saliva sampling is noninvasive and has a great potential to be used for studies aimed at analysing the magnitude, time course, and variance in immune responses, including inflammation after vaccination. Based on a literature survey of inflammatory biomarkers that can be determined in saliva and an analysis of how these biomarkers could help to understand the mechanisms and dynamics of immune reactivity and inflammation, we propose that the saliva-based approach might have potential to add substantial value to clinical studies, particularly in vulnerable populations such as infants, toddlers, and ill individuals. PMID:27022211

  17. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis

    PubMed Central

    Khandpur, Ritika; Carmona-Rivera, Carmelo; Vivekanandan-Giri, Anuradha; Gizinski, Alison; Yalavarthi, Srilakshmi; Knight, Jason S.; Friday, Sean; Li, Sam; Patel, Rajiv M.; Subramanian, Venkataraman; Thompson, Paul; Chen, Pojen; Fox, David A.; Pennathur, Subramaniam; Kaplan, Mariana J.

    2013-01-01

    The early events leading to the development of rheumatoid arthritis (RA) remain unclear but formation of autoantibodies to citrullinated antigens (ACPA) is considered a key pathogenic phenomenon. Neutrophils isolated from patients with various autoimmune diseases display enhanced extracellular trap formation (NETs), a phenomenon that externalizes autoantigens and immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and synovial fluid RA neutrophils, compared to neutrophils from healthy controls and from patients with osteoarthritis. Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. During NETosis, neutrophils externalized citrullinated autoantigens implicated in RA pathogenesis, whereas anti-citrullinated vimentin antibodies potently induced NET formation. The inflammatory cytokines IL-17A and TNF-α induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease. PMID:23536012

  18. Deer Bone Oil Extract Suppresses Lipopolysaccharide-Induced Inflammatory Responses in RAW264.7 Cells.

    PubMed

    Choi, Hyeon-Son; Im, Suji; Park, Yooheon; Hong, Ki-Bae; Suh, Hyung Joo

    2016-01-01

    The aim of this study was to investigate the effect of deer bone oil extract (DBOE) on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. DBOE was fractionated by liquid-liquid extraction to obtain two fractions: methanol fraction (DBO-M) and hexane fraction (DBO-H). TLC showed that DBO-M had relatively more hydrophilic lipid complexes, including unsaturated fatty acids, than DBOE and DBO-H. The relative compositions of tetradecenoyl carnitine, α-linoleic acid, and palmitoleic acid increased in the DBO-M fraction by 61, 38, and 32%, respectively, compared with DBOE. The concentration of sugar moieties was 3-fold higher in the DBO-M fraction than DBOE and DBO-H. DBO-M significantly decreased LPS-induced nitric oxide (NO) production in RAW264.7 cells in a dose-dependent manner. This DBO-M-mediated decrease in NO production was due to downregulation of mRNA and protein levels of inducible nitric oxide synthase (iNOS). In addition, mRNA expression of pro-inflammatory mediators, such as cyclooxygenase (COX-2), interleukin (IL)-1β, and IL-12β, was suppressed by DBO-M. Our data showed that DBO-M, which has relatively higher sugar content than DBOE and DBO-H, could play an important role in suppressing inflammatory responses by controlling pro-inflammatory cytokines and mediators. PMID:27040632

  19. The Sbi Protein Contributes to Staphylococcus aureus Inflammatory Response during Systemic Infection

    PubMed Central

    Gonzalez, Cintia Daniela; Garófalo, Ailin; Gómez, Marisa I.

    2015-01-01

    Staphylococcus aureus is an important human pathogen that causes infections that may present high morbidity and mortality. Among its many virulence factors protein A (SpA) and Staphylococcal binding immunoglobulin protein (Sbi) bind the Fc portion of IgG interfering with opsonophagocytosis. We have previously demonstrated that SpA interacts with the TNF-α receptor (TNFR) 1 through each of the five IgG binding domains and induces the production of pro-inflammatory cytokines and chemokines. The IgG binding domains of Sbi are homologous to those of SpA, which allow us to hypothesize that Sbi might also have a role in the inflammatory response induced by S. aureus. We demonstrate that Sbi is a novel factor that participates in the induction of the inflammatory response during staphylococcal infections via TNFR1 and EGFR mediated signaling as well as downstream MAPKs. The expression of Sbi significantly contributed to IL-6 production and modulated CXCL-1 expression as well as neutrophil recruitment to the site of infection, thus demonstrating for the first time its relevance as a pro-inflammatory staphylococcal antigen in an in vivo model. PMID:26126119

  20. Evidence that mesothelial cells regulate the acute inflammatory response in talc pleurodesis.

    PubMed

    Marchi, E; Vargas, F S; Acencio, M M; Antonangelo, L; Genofre, E H; Teixeira, L R

    2006-11-01

    Intrapleural instillation of talc is used to produce pleurodesis in cases of recurrent malignant pleural effusions. The mechanisms by which pleurodesis is produced remain unknown but may involve either injury or activation of the mesothelium. The aim of the current study was to assess the inflammatory response of pleural mesothelial cells to talc in an experimental model in rabbits. A group of 10 rabbits were injected intrapleurally with talc (200 mg.kg(-1)) and undiluted pleural fluid was collected after 6, 24 or 48 h for measurement of interleukin (IL)-8, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1. Samples of pleura were studied to assess the inflammatory infiltrate and mesothelial cell viability. The pleural fluid IL-8 concentration peaked at 6 h, whereas VEGF and TGF-beta1 concentrations increased steadily over 48 h. Immunohistochemistry for cytokeratin showed a preserved layer of mesothelial cells despite the intense inflammatory pleural reaction. In conclusion, it is proposed that the mesothelial cell, although injured by the talc, may actively mediate the primary inflammatory pleural response in talc-induced pleurodesis. PMID:16870666

  1. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response.

    PubMed

    Hong, Hyun Sook; Son, Youngsook

    2014-10-10

    Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel ability to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T(reg) and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases. PMID:25264193

  2. Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

    PubMed Central

    Gerö, Domokos; Szoleczky, Petra; Módis, Katalin; Pribis, John P.; Al-Abed, Yousef; Yang, Huan; Chevan, Sangeeta; Billiar, Timothy R.; Tracey, Kevin J.; Szabo, Csaba

    2013-01-01

    High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. PMID:23799067

  3. BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.

    PubMed

    Chen, Jinjing; Wang, Zhen; Hu, Xiangming; Chen, Ruichuan; Romero-Gallo, Judith; Peek, Richard M; Chen, Lin-Feng

    2016-05-15

    Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer. PMID:27084101

  4. Functional Role of Milk Fat Globule-Epidermal Growth Factor VIII in Macrophage-Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases

    PubMed Central

    2016-01-01

    Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs. PMID:27429513

  5. Endothelial Inflammatory Transcriptional Responses Induced by Plasma Following Inhalation of Diesel Emissions

    PubMed Central

    Schisler, Jonathan C.; Ronnebaum, Sarah M.; Madden, Michael; Channell, Meghan M.; Campen, Matthew J.; Willis, Monte S.

    2016-01-01

    Background Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology. Objectives Previously, we found that canonical inflammatory response transcripts were elevated in cultured endothelial cells treated with plasma obtained after exposure compared with pre-exposure samples or filtered air (sham) exposures. While the findings confirmed the presence of bioactive factor(s) in the plasma after diesel inhalation, we wanted to better examine the complete genomic response to investigate 1) major responsive transcripts and 2) collected response pathways and ontogeny that may help to refine this method and inform the pathogenesis. Methods We assayed endothelial RNA with gene expression microarrays, examining the responses of cultured endothelial cells to plasma obtained from 6 healthy human subjects exposed to 100 μg/m3 diesel exhaust or filtered air for 2 h on separate occasions. In addition to pre-exposure baseline samples, we investigated samples obtained immediately-post and 24h-post exposure. Results Microarray analysis of the coronary artery endothelial cells challenged with plasma identified 855 probes that changed over time following diesel exhaust exposure. Over-representation analysis identified inflammatory cytokine pathways were upregulated both at the 2 and 24 h condition. Novel pathways related to FOX transcription factors and secreted extracellular factors were also identified in the microarray analysis. Conclusions These outcomes are consistent with our recent findings that plasma contains bioactive and inflammatory factors following pollutant inhalation. The specific study design implicates a novel pathway related to inflammatory blood borne components that may drive the extrapulmonary toxicity of ambient air pollutants. PMID:25942053

  6. The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom.

    PubMed

    Moreira, Vanessa; Teixeira, Catarina; Borges da Silva, Henrique; D'Império Lima, Maria Regina; Dos-Santos, Maria Cristina

    2016-08-01

    Envenomation by snakes of the species Bothrops atrox induces local and systemic effects. Local effects include drastic tissue damage and a marked inflammatory response as a result of the synthesis and release of a variety of protein and lipid mediators. Toll-like receptor (TLR) signaling pathways can play an important role in this response, leading to synthesis of these inflammatory mediators. This study investigated the influence of TLR2 on the acute inflammatory response induced by Bothrops atrox venom. Wild-type C57BL/6 mice (WT) and TLR2 gene knockout mice (TLR2(-/-)) were injected with Bothrops atrox venom (BaV), and the following responses to the venom were assessed in peritoneal exudate: leukocyte accumulation; release of mediators, including CCL-2, IL-10, IL-1β, IL-6 and LTB4; protein expression of COX-1 and COX-2; and quantification of their products PGE2 and TXA2. After injection with BaV, the TLR2(-/-) mice (TLR2(-/-)BaV) had higher levels of IL-6 and CCL-2 than WT animals kept under the same conditions (WTBaV), together with an accumulation of polymorphonuclear leukocytes (PMNs), inhibition of IL-1β and LTB4 and reduced mononuclear leukocyte influx. However, no significant differences in COX-2 protein expression or PGE2, TXA2 and IL-10 production between the TLR2(-/-)BaV and WTBav animals were observed. Together, these results indicate that the signaling pathway activated by TLR2 acts by modulating the induced inflammatory response to BaV through the direct action of venom-associated molecular patterns (VAMPs) or indirectly by forming damage-associated molecular patterns (DAMPs) and that this may have important therapeutic implications. PMID:27109323

  7. Central inflammatory response to experimental stroke is inhibited by a neuroprotective dose of dietary soy.

    PubMed

    Shambayati, Maryam; Patel, Maharshi; Ma, Yulin; Cunningham, Rebecca L; Schreihofer, Derek A

    2014-12-17

    Dietary soy and soy isoflavones are neuroprotective in experimental cerebral ischemia. Because the isoflavones in soy that are responsible for this neuroprotective effect act as phytoestrogens, we hypothesized that they would mimic the beneficial effects of estrogens on the innate inflammatory response to cerebral ischemia. Ovariectomized Sprague-Dawley rats were fed a soy free diet or a diet containing high dietary levels of soy for 5 weeks, after which they were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min. Dietary soy was associated with a reduced inflammatory response in the cerebral cortex during the acute innate period 4 and 24h after tMCAO, including significant (>2-fold) reductions in interleukins 1 beta, 2, and 13, and the chemokine CXCL1. However, there was no effect of soy on tumor necrosis factor-alpha or interferon-gamma. Dietary soy was also associated with a 40 percent reduction in the nuclear translocation of p65 nuclear factor kappa B despite an increase in the expression of p65 RELA mRNA. In support of an early effect on the innate immune response to stroke, soy-fed rats had 44 percent fewer activated microglia in the infarct core than soy free rats. Interestingly, despite increased expression following injury, the steady state mRNA levels of inflammatory factors were not altered in soy-fed rats even though inflammatory proteins were. These data suggest that dietary soy isoflavones, like estrogens, inhibit of the innate immune response to injury. However, post-transcriptional mechanisms may play an important role in the mechanism of this action. Coupled with previously published data, these results support an early and rapid effect of dietary soy on the evolution of brain injury following stroke. PMID:25261694

  8. Novel markers of inflammatory response and hepatic dysfunction in canine leishmaniasis.

    PubMed

    Tonin, Alexandre A; Calado, Andréa M C; Bottari, Nathieli B; Dalenogare, Diéssica; Thomé, Gustavo R; Duarte, Thiago; Duarte, Marta M M F; Morsch, Vera M; Schetinger, Maria R C; Alves, Leucio C; Tinucci-Costa, Mirela; Da Silva, Aleksandro S

    2016-02-01

    Dogs are the main host of Leishmania infantum, and the clinical presentation may range from asymptomatic to systemic manifestations. The immune mechanisms in infected, but clinically healthy dogs, prevails Th1 response mediated by cytokines. In this sense, adenosine deaminase (ADA) and butyrylcholinesterase (BChE) are considered as key enzymes in several physiological processes, including the modulation of inflammatory process. Considering the variable immune response against Leishmania and the known participation of ADA and BChE, the aim of this study was to assess the relation between these two enzymes with the inflammatory response as well as hepatic function in dogs naturally infected with L. infantum. For this purpose, the activity of ADA and BChE was assessed in sera of 24 dogs naturally infected with L. infantum, plus 17 healthy dogs. The naturally infected dogs had clinical signs compatible with leishmaniasis and sera activities of ADA (P<0.01) and BChE (P<0.05) decreased, when compared to the healthy group. The reduction of ADA activity probably represented an effect on inflammatory response, especially due to the decreased hydrolysis of extracellular adenosine, might in order to protect against tissue damage and, also, setting a down-regulation on pro-inflammatory cytokines. BChE enzyme had no effect on modulating the immune response in leishmaniasis, but it decreased, a fact may related to deficiency of synthesis in the liver. Therefore, ADA and BChE activities reduced probably in order to protect against extra tissue damage and due failure in synthesis, respectively. PMID:26454326

  9. Vagal nerve stimulation blocks peritoneal macrophage inflammatory responsiveness after severe burn injury.

    PubMed

    Lopez, Nicole E; Krzyzaniak, Michael; Costantini, Todd W; De Maio, Antonio; Baird, Andrew; Eliceiri, Brian P; Coimbra, Raul

    2012-08-01

    Large surface area burn injuries lead to activation of the innate immune system, which can be blocked by parasympathetic inputs mediated by the vagus nerve. We hypothesized that vagal nerve stimulation (VNS) would alter the inflammatory response of peritoneal macrophages after severe burn injury. Male BALB/c mice underwent right cervical VNS before 30% total body surface area steam burn and were compared with animals subjected to burn alone. Peritoneal macrophages were harvested at several time points following injury and exposed to lipopolysaccharide (LPS) in culture conditions. The inflammatory response of peritoneal macrophages was measured by analyzing changes in nuclear factor κB p65 phosphorylation using flow cytometry. We found that peritoneal macrophages isolated from mice subjected to burn injury were hyperresponsive to LPS challenge, suggesting burn-induced macrophage activation. We identified a protective role for VNS in blocking peritoneal macrophage activation. Analysis of the phosphorylation state of nuclear factor κB pathway mediator, p65 Rel A, revealed a VNS-mediated reduction in p65 phosphorylation levels after exposure to LPS compared with burn alone. In combination, these studies suggest VNS mediates the inflammatory response in peritoneal macrophages by affecting the set point of LPS responsiveness. PMID:22683732

  10. miR-709 modulates LPS-induced inflammatory response through targeting GSK-3β.

    PubMed

    Li, Ming; Chen, Hu; Chen, Luxi; Chen, Yaosheng; Liu, Xiaohong; Mo, Delin

    2016-07-01

    MicroRNAs (miRNAs) are endogenous small non-coding RNAs which modulate gene expression at the post-transcriptional level by either translational inhibition or mRNA degradation. MicroRNAs play important roles in both innate and adaptive immune response, including TLR-triggered immune response. In this study, we found that the expression of miR-709 was up-regulated in primary macrophage and RAW264.7 cells during the stimulation of LPS. Overexpression of miR-709 in RAW264.7 cells led to reduced production and gene expression of inflammatory cytokines (IL-6, TNF-α, IL-1β) during activation by LPS, whereas knockdown of miR-709 had completely opposite effects. We used bioinformatics and experimental techniques to demonstrate that GSK-3β is a direct target of miR-709. miR-709 mimics decreased GSK-3β protein but not mRNA level. We also found that miR-709 regulated the LPS-induced inflammatory response by targeting GSK-3β and elevating β-catenin. In conclusion, our data revealed a novel role for miR-709 in regulation of inflammatory response by targeting GSK-3β. PMID:27232654

  11. Absence of inflammatory response from upper airway epithelial cells after X irradiation.

    PubMed

    Reiter, R; Deutschle, T; Wiegel, T; Riechelmann, H; Bartkowiak, D

    2009-03-01

    Radiotherapy of head and neck tumors causes adverse reactions in normal tissue, especially mucositis. The dose- and time-dependent response of upper airway cells to X radiation should be analyzed in terms of the pro-inflammatory potential. Immortalized BEAS-2B lung epithelial cells were treated with 2, 5 and 8 Gy. Out of 1232 genes, those that were transcribed differentially after 2, 6 and 24 h were assigned to biological themes according to the Gene Ontology Consortium. Enrichment of differentially regulated gene clusters was determined with GOTree ( http://bioinfo.vanderbilt.edu/gotm ). Eleven cytokines were measured in culture supernatants. The cell cycle response up to 24 h and induction of apoptosis up to 4 days after exposure were determined by flow cytometry. A significant dose- and time-dependent gene activation was observed for the categories response to DNA damage, oxidative stress, cell cycle arrest and cell death/apoptosis but not for immune/inflammatory response. This correlated with functional G(2) arrest and apoptosis. Pro-inflammatory cytokines accumulated in supernatants of control cells but not of X-irradiated cells. The complex gene expression pattern of X-irradiated airway epithelial cells is accompanied by cell cycle arrest and induction of apoptosis. In vivo, this may impair the epithelial barrier. mRNA and protein expression suggest at most an indirect contribution of epithelial cells to early radiogenic mucositis. PMID:19267554

  12. The absence of microbiota delays the inflammatory response to Cryptococcus gattii.

    PubMed

    Costa, Marliete Carvalho; Santos, Julliana Ribeiro Alves; Ribeiro, Maira Juliana Andrade; Freitas, Gustavo José Cota de; Bastos, Rafael Wesley; Ferreira, Gabriella Freitas; Miranda, Aline Silva; Arifa, Raquel Duque Nascimento; Santos, Patrícia Campi; Martins, Flaviano Dos Santos; Paixão, Tatiane Alves; Teixeira, Antonio Lúcio; Souza, Danielle G; Santos, Daniel Assis

    2016-06-01

    The inflammatory response plays a crucial role in infectious diseases, and the intestinal microbiota is linked to maturation of the immune system. However, the association between microbiota and the response against fungal infections has not been elucidated. Our aim was to evaluate the influence of microbiota on Cryptococcus gattii infection. Germ-free (GF), conventional (CV), conventionalized (CVN-mice that received feces from conventional animals), and LPS-stimulated mice were infected with C. gattii. GF mice were more susceptible to infection, showing lower survival, higher fungal burden in the lungs and brain, increased behavioral changes, reduced levels of IFN-γ, IL-1β and IL-17, and lower NFκBp65 phosphorylation compared to CV mice. Low expression of inflammatory cytokines was associated with smaller yeast cells and polysaccharide capsules (the main virulence factor of C. gattii) in the lungs, and less tissue damage. Furthermore, macrophages from GF mice showed reduced ability to engulf, produce ROS, and kill C. gattii. Restoration of microbiota (CVN mice) or LPS administration made GF mice more responsive to infection, which was associated with increased survival and higher levels of inflammatory mediators. This study is the first to demonstrate the influence of microbiota in the host response against C. gattii. PMID:27083265

  13. Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses.

    PubMed

    Kim, Ha Ryong; Lee, Kyuhong; Park, Chang We; Song, Jeong Ah; Shin, Da Young; Park, Yong Joo; Chung, Kyu Hyuck

    2016-03-01

    Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form

  14. Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.

    PubMed

    Park, Soo-Yeon; Kim, Mi-Jeong; Kim, Young Jun; Lee, Yoo-Hyun; Bae, Donghyuk; Kim, Sunoh; Na, Younghwa; Yoon, Ho-Geun

    2015-04-01

    Several recent studies have reported an association between neurodegeneration and histone modifications, such as acetylation, deacetylation and methylation. In addition, questions have been raised regarding a potential functional role for the histone acetylation enzymes in β-amyloid (Aβ)-mediated neurotoxicity, particularly the p300/CBP-associated factor (PCAF) enzyme. We recently reported the potential utility of a PCAF inhibitor in the suppression of Aβ-induced neuronal cell death, although the in vivo effectiveness of the PCAF inhibitor remained unclear. In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats. In conclusion, our results demonstrate that this selective PCAF inhibitor has the potential to reduce the neuroinflammatory response induced by Aβ. PMID:25672970

  15. Evasion and interference: intracellular pathogens modulate caspase-dependent inflammatory responses.

    PubMed

    Stewart, Mary K; Cookson, Brad T

    2016-06-01

    Pathogens have evolved to complete the virulence cycle of colonization, replication and dissemination in intimate association with a complex network of extracellular and intracellular surveillance systems that guard tissue spaces. In this Review, we discuss the strategies used by bacteria and viruses to evade or inhibit intracellular detection that is coupled to pro-inflammatory caspase-dependent protective responses. Such strategies include alterations of lipopolysaccharide (LPS) structures, the regulated expression of components of type III secretion systems, and the utilization of proteins that inhibit inflammasome formation, the enzymatic activity of caspases and cytokine signalling. Inflammation is crucial in response to exposure to pathogens, but is potentially damaging and thus tightly regulated. The threshold for the activation of pro-inflammatory caspases is determined by the immediate stimulus in the context of previous signals. Pathogen, genetic and situational factors modulate this threshold, which determines the ability of the host to resist infection while minimizing harm. PMID:27174147

  16. Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases.

    PubMed

    Yue, Li; Yao, Hongwei

    2016-08-01

    Mitochondria are dynamic organelles, which couple the various cellular processes that regulate metabolism, cell proliferation and survival. Environmental stress can cause mitochondrial dysfunction and dynamic changes including reduced mitochondrial biogenesis, oxidative phosphorylation and ATP production, as well as mitophagy impairment, which leads to increased ROS, inflammatory responses and cellular senescence. Oxidative stress, inflammation and cellular senescence all have important roles in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and bronchopulmonary dysplasia. In this review, we discuss the current state on how mitochondrial dysfunction affects inflammatory responses and cellular senescence, the mechanisms of mitochondrial dysfunction underlying the pathogenesis of chronic lung diseases and the potential of mitochondrial transfer and replacement as treatments for these diseases. PMID:27189175

  17. Ultrasonographic approach to diagnosis of fetal inflammatory response syndrome: a tool for at-risk fetuses?

    PubMed

    Mastrolia, Salvatore Andrea; Erez, Offer; Loverro, Giuseppe; Di Naro, Edoardo; Weintraub, Adi Yehuda; Tirosh, Dan; Baron, Joel; Hershkovitz, Reli

    2016-07-01

    Preterm parturition is a syndrome that may result from many underlying mechanisms. Infection and inflammation are the prominent ones. Intrauterine infection and inflammation have an effect akin to sepsis, and that is similar to systemic inflammatory response in adults. Indeed, there is evidence to support the association of a fetal inflammatory response syndrome (FIRS) to systemic infection and inflammation. The utilization of invasive procedures for the prenatal diagnosis of FIRS is associated with a risk for complications resulting from the invasive method. The progress in the imaging quality of obstetrical ultrasound and the development of novel methods for functional anatomical assessment of the fetal organs may help to identify, noninvasively, fetuses at risk for FIRS in patients presenting with preterm labor. We review the studies describing advanced sonographic modalities and the imaging findings in the heart, thymus, kidney, adrenal glands, and spleen of these fetuses. PMID:26821337

  18. Topology and dynamics of signaling networks: in search of transcriptional control of the inflammatory response.

    PubMed

    Androulakis, Ioannis P; Kamisoglu, Kubra; Mattick, John S

    2013-01-01

    Over the past several decades, to develop a fundamental understanding of inflammation's progression, research has focused on extracellular mediators, such as cytokines, as characteristic components of inflammatory response. These efforts have recently been complemented by advances in proteomics that allow analysis of multiple signaling proteins in parallel, to provide more complete mechanistic models of inflammation. In this review, we discuss various techniques for assessing protein activity, as well as computational techniques that are well suited for interpreting large amounts of proteomic data to generate signaling networks or for modeling the dynamics of known network interactions. We also discuss examples that explore these experimental and computational techniques in tandem to generate signaling networks under various conditions and that link those networks to transcriptional activity. Further advancements in this field will likely provide an explicit description of inflammatory response, paving the way for better diagnostics and therapies in clinic. PMID:23862674

  19. Corpse Engulfment Generates a Molecular Memory that Primes the Macrophage Inflammatory Response.

    PubMed

    Weavers, Helen; Evans, Iwan R; Martin, Paul; Wood, Will

    2016-06-16

    Macrophages are multifunctional cells that perform diverse roles in health and disease. Emerging evidence has suggested that these innate immune cells might also be capable of developing immunological memory, a trait previously associated with the adaptive system alone. While recent studies have focused on the dramatic macrophage reprogramming that follows infection and protects against secondary microbial attack, can macrophages also develop memory in response to other cues? Here, we show that apoptotic corpse engulfment by Drosophila macrophages is an essential primer for their inflammatory response to tissue damage and infection in vivo. Priming is triggered via calcium-induced JNK signaling, which leads to upregulation of the damage receptor Draper, thus providing a molecular memory that allows the cell to rapidly respond to subsequent injury or infection. This remarkable plasticity and capacity for memory places macrophages as key therapeutic targets for treatment of inflammatory disorders. PMID:27212238

  20. Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-κB pathway and reduction of anti-inflammatory mediator expression in the kidney

    PubMed Central

    Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan; Chen, Kejie

    2015-01-01

    Nickel (Ni) or Ni compounds target a number of organs and produce multiple toxic effects. Kidney is the major organ for Ni accumulation and excretion. There are no investigations on the Ni- or Ni compounds-induced renal inflammatory responses in human beings and animals at present. Therefore, we determined NiCl2-caused alteration of inflammatory mediators, and functional damage in the broiler's kidney by the methods of biochemistry, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Dietary NiCl2 in excess of 300 mg/kg caused the renal inflammatory responses that characterized by increasing mRNA expression levels of the pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) via the activation of nucleic factor κB (NF-κB), and decreasing mRNA expression levels of the anti-inflammatory mediators including interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-13 (IL-13). Concurrently, NiCl2 caused degeneration, necrosis and apoptosis of the tubular cells, which was consistent with the alteration of renal function parameters including elevated alkaline phosphatase (AKP) activity, and reduced activities of sodium-potassium adenosine triphosphatase (Na+/K+-ATPase), calcium adenosine triphosphatase (Ca2+-ATPase), lactic dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) in the kidney. The above-mentioned results present that the activation of NF-κB pathway and reduction of anti-inflammatory mediator expression are main mechanisms of NiCl2-caused renal inflammatory responses and that the renal function is decreased or impaired after NiCl2-treated. PMID:26417933

  1. Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-κB pathway and reduction of anti-inflammatory mediator expression in the kidney.

    PubMed

    Guo, Hongrui; Deng, Huidan; Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan; Chen, Kejie

    2015-10-01

    Nickel (Ni) or Ni compounds target a number of organs and produce multiple toxic effects. Kidney is the major organ for Ni accumulation and excretion. There are no investigations on the Ni- or Ni compounds-induced renal inflammatory responses in human beings and animals at present. Therefore, we determined NiCl2-caused alteration of inflammatory mediators, and functional damage in the broiler's kidney by the methods of biochemistry, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Dietary NiCl2 in excess of 300 mg/kg caused the renal inflammatory responses that characterized by increasing mRNA expression levels of the pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) via the activation of nucleic factor κB (NF-κB), and decreasing mRNA expression levels of the anti-inflammatory mediators including interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-13 (IL-13). Concurrently, NiCl2 caused degeneration, necrosis and apoptosis of the tubular cells, which was consistent with the alteration of renal function parameters including elevated alkaline phosphatase (AKP) activity, and reduced activities of sodium-potassium adenosine triphosphatase (Na(+)/K(+)-ATPase), calcium adenosine triphosphatase (Ca(2+)-ATPase), lactic dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) in the kidney. The above-mentioned results present that the activation of NF-κB pathway and reduction of anti-inflammatory mediator expression are main mechanisms of NiCl2-caused renal inflammatory responses and that the renal function is decreased or impaired after NiCl2-treated. PMID:26417933

  2. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

    SciTech Connect

    Hong, Hyun Sook; Son, Youngsook

    2014-10-10

    Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel ability to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.

  3. Diminazene Aceturate (Berenil) Modulates the Host Cellular and Inflammatory Responses to Trypanosoma congolense Infection

    PubMed Central

    Onyilagha, Chukwunonso; Singh, Rani; Jia, Ping; Uzonna, Jude E.

    2012-01-01

    Background Trypanosoma congolense are extracellular and intravascular blood parasites that cause debilitating acute or chronic disease in cattle and other domestic animals. Diminazene aceturate (Berenil) has been widely used as a chemotherapeutic agent for trypanosomiasis in livestock since 1955. As in livestock, treatment of infected highly susceptible BALB/c mice with Berenil leads to rapid control of parasitemia and survival from an otherwise lethal infection. The molecular and biochemical mechanisms of action of Berenil are still not very well defined and its effect on the host immune system has remained relatively unstudied. Here, we investigated whether Berenil has, in addition to its trypanolytic effect, a modulatory effect on the host immune response to Trypanosoma congolense. Methodology/Principal Findings BALB/c and C57BL/6 mice were infected intraperitoneally with T. congolense, treated with Berenil and the expression of CD25 and FoxP3 on splenic cells was assessed directly ex vivo. In addition, serum levels and spontaneous and LPS-induced production of pro-inflammatory cytokines by splenic and hepatic CD11b+ cells were determined by ELISA. Berenil treatment significantly reduced the percentages of CD25+ cells, a concomitant reduction in the percentage of regulatory (CD4+Foxp3+) T cells and a striking reduction in serum levels of disease exacerbating pro-inflammatory cytokines including IL-6, IL-12, TNF and IFN-γ. Furthermore, Berenil treatment significantly suppressed spontaneous and LPS-induced production of inflammatory cytokines by splenic and liver macrophages and significantly ameliorated LPS-induced septic shock and the associated cytokine storm. Conclusions/Significance Collectively, these results provide evidence that in addition to its direct trypanolytic effect, Berenil also modulates the host immune response to the parasite in a manner that dampen excessive immune activation and production of pathology-promoting pro-inflammatory cytokines

  4. Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD

    PubMed Central

    2013-01-01

    Background Rhinovirus (RV) is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations, and primarily infects bronchial epithelial cells. Immune responses from BECs to RV infection are critical in limiting viral replication, and remain unclear in COPD. The objective of this study is to investigate innate immune responses to RV infection in COPD primary BECs (pBECs) in comparison to healthy controls. Methods Primary bronchial epithelial cells (pBECs) from subjects with COPD and healthy controls were infected with RV-1B. Cells and cell supernatant were collected and analysed using gene expression microarray, qPCR, ELISA, flow cytometry and titration assay for viral replication. Results COPD pBECs responded to RV-1B infection with an increased expression of antiviral and pro-inflammatory genes compared to healthy pBECs, including cytokines, chemokines, RNA helicases, and interferons (IFNs). Similar levels of viral replication were observed in both disease groups; however COPD pBECs were highly susceptible to apoptosis. COPD pBECs differed at baseline in the expression of 9 genes, including calgranulins S100A8/A9, and 22 genes after RV-1B infection including the signalling proteins pellino-1 and interleukin-1 receptor associated kinase 2. In COPD, IFN-β/λ1 pre-treatment did not change MDA-5/RIG-I and IFN-β expression, but resulted in higher levels IFN-λ1, CXCL-10 and CCL-5. This led to reduced viral replication, but did not increase pro-inflammatory cytokines. Conclusions COPD pBECs elicit an exaggerated pro-inflammatory and antiviral response to RV-1B infection, without changing viral replication. IFN pre-treatment reduced viral replication. This study identified novel genes and pathways involved in potentiating the inflammatory response to RV in COPD. PMID:23384071

  5. Lipopolysaccharide induces the expression of an autocrine prolactin loop enhancing inflammatory response in monocytes

    PubMed Central

    2013-01-01

    Background Prolactin from pituitary gland helps maintain homeostasis but it is also released in immune cells where its function is not completely understood. Pleiotropic functions of prolactin (PRL) might be mediated by different isoforms of its receptor (PRLr). Methods The aim of this study was to investigate the relationship between the eventual synthesis of PRL and PRLr isoforms with the inflammatory response in monocytes. We used THP-1 and monocytes isolated from healthy subjects stimulated with lipopolysaccharide (LPS). Western blot, real time PCR and immunocytochemistry were performed to identify both molecules. The bioactivity of the PRL was assessed using a bioassay and ELISA to detect pro inflammatory cytokines. Results PRLr mRNA and PRL mRNA were synthesized in THP-1 monocytes activated with LPS with peaks of 300-fold and 130-fold, respectively. The long (100 kDa) and the intermediate (50 kDa) isoforms of PRLr and big PRL (60 kDa) were time-dependent upregulated for monocytes stimulated with LPS. This expression was confirmed in monocytes from healthy subjects. The PRLr intermediate isoform and the big PRL were found soluble in the culture media and later in the nucleus in THP-1 monocytes stimulated with LPS. Big PRL released by monocytes showed bioactivity in Nb2 Cells, and both PRL and PRLr, synthesized by monocytes were related with levels of nitrites and proinflammatory citokines. Conclusions Our results suggest the expression of a full-autocrine loop of PRL enhances the inflammatory response in activated monocytes. This response mediated by big PRL may contribute to the eradication of potential pathogens during innate immune response in monocytes but may also contribute to inflammatory disorders. PMID:23731754

  6. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

    SciTech Connect

    Tilton, Susan C.; Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C.; Lee, K. Monica; Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A.

    2013-03-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung

  7. SWCNT suppress inflammatory mediator responses in human lung epithelium in vitro

    SciTech Connect

    Herzog, Eva Byrne, Hugh J.; Casey, Alan; Davoren, Maria; Lenz, Anke-Gabriele; Maier, Konrad L.; Duschl, Albert; Oostingh, Gertie Janneke

    2009-02-01

    Single-walled carbon nanotubes have gained enormous popularity due to a variety of potential applications which will ultimately lead to increased human and environmental exposure to these nanoparticles. This study was carried out in order to evaluate the inflammatory response of immortalised and primary human lung epithelial cells (A549 and NHBE) to single-walled carbon nanotube samples (SWCNT). Special focus was placed on the mediating role of lung surfactant on particle toxicity. The toxicity of SWCNT dispersed in cell culture medium was compared to that of nanotubes dispersed in dipalmitoylphosphatidylcholine (DPPC, the main component of lung lining fluid). Exposure was carried out for 6 to 48 h with the latter time-point showing the most significant responses. Moreover, exposure was performed in the presence of the pro-inflammatory stimulus tumour necrosis factor-{alpha} (TNF-{alpha}) in order to mimic exposure of stimulated cells, as would occur during infection. Endpoints evaluated included cell viability, proliferation and the analysis of inflammatory mediators such as interleukin (IL)-8, IL-6, TNF-{alpha} and macrophage chemoattractant protein-1 (MCP-1). Crocidolite asbestos was included as a well characterised, toxic fibre control. The results of this study showed that HiPco SWCNT samples suppress inflammatory responses of A549 and NHBE cells. This was also true for TNF-{alpha} stimulated cells. The use of DPPC improved the degree of SWCNT dispersion in A549 medium and in turn, leads to increased particle toxicity, however, it was not shown to modify NHBE cell responses.

  8. Inflammatory responses to induced infectious endometritis in mares resistant or susceptible to persistent endometritis

    PubMed Central

    2012-01-01

    Background The objective of the study was to evaluate the gene expression of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-α, IL-1 receptor antagonist [ra] and serum amyloid A (SAA) in endometrial tissue and circulating leukocytes in response to uterine inoculation of 105 colony forming units (CFU) Escherichia coli in mares. Before inoculation, mares were classified as resistant or susceptible to persistent endometritis based on their uterine inflammatory response to infusion of 109 killed spermatozoa and histological assessment of the endometrial quality. Endometrial biopsies were obtained 3, 12, 24 and 72 hours (h) after bacterial inoculation and blood samples were obtained during the 7 day period post bacterial inoculation. Expression levels of cytokines and SAA were determined by quantitative real-time reverse transcriptase PCR (qRT-PCR). Results Compared to levels in a control biopsy (obtained in the subsequent estrous), resistant mares showed an up-regulation of IL-1β, IL-6, IL-8 and TNF-α at 3 h after E. coli inoculation, while susceptible mares showed increased gene expression of IL-6 and IL-1ra. Susceptible mares had a significant lower gene expression of TNF-α,IL-6 and increased expression of IL-1ra 3 h after E. coli inoculation compared to resistant mares. Susceptible mares showed a sustained and prolonged inflammatory response with increased gene expression levels of IL-1β, IL-8, IL-1ra and IL-1β:IL-1ra ratio throughout the entire study period (72 h), whereas levels in resistant mares returned to estrous control levels by 12 hours. Endometrial mRNA transcripts of IL-1β and IL-1ra were significantly higher in mares with heavy uterine bacterial growth compared to mares with no/mild growth. All blood parameters were unaffected by intrauterine E. coli infusion, except for a lower gene expression of IL-10 at 168 h and an increased expression of IL-1ra at 48 h observed in susceptible mares compared to

  9. Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses

    PubMed Central

    Chen, Qian-Qian; Yan, Li; Wang, Chang-Zheng; Wang, Wei-Hua; Shi, Hui; Su, Bin-Bin; Zeng, Qing-Huan; Du, Hai-Tao; Wan, Jun

    2013-01-01

    AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-17, IL-4, IL-10, and transforming growth factor (TGF-β). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORγt), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-α, IFN-γ, T-bet; IL-6, IL-17, RORγt), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4+CD25+Foxp3

  10. Sex-specific social regulation of inflammatory responses and sickness behaviors

    PubMed Central

    Yee, Jason R.; Prendergast, Brian J.

    2010-01-01

    In many mammals, the availability of familiar conspecifics in the home environment can affect immune function and morbidity. Numerous sex differences exist in immune responses, but whether the social environment impacts the immune system differently in males and females is not fully understood. This study examined behavioral and physiological responses to simulated bacterial infection in adult male and female Wistar rats housed either with 3 same-sex non-siblings (Group) or alone (Isolate). Rats were injected with bacterial lipopolysaccharide (E. coli LPS; 150 µg/kg, i.p.), and behavioral (orectic, locomotor, and social) and physiological (thermoregulatory, cytokine, and corticosterone) inflammatory responses were measured. Among males, LPS-induced fever, suppressed locomotor activity, and inhibited feeding behavior and the magnitude of these responses were greater in Isolate relative to Group housed individuals. In contrast, among females group housing exacerbated behavioral and physiological symptoms of simulated infection. LPS treatments elicited IL-1β production in all groups, but plasma IL-1β concentrations were higher and peaked earlier in Isolate relative to Group males, and in Group relative to Isolate females. Furthermore, plasma concentrations of TNFα and IL-2 were higher in Group relative to Isolate males. Plasma corticosterone concentrations did not vary as a function of social housing conditions. Together, the data indicate that the social environment markedly influences innate immune responses. Group housing exacerbates inflammatory responses and sickness behaviors in females, but attenuates these responses in males. These sex differences are mediated in part by differential effects of the social environment on pro- and anti-inflammatory cytokine production. PMID:20303405

  11. Sleep Loss and the Inflammatory Response in Mice Under Chronic Environmental Circadian Disruption

    PubMed Central

    Castanon-Cervantes, Oscar; Natarajan, Divya; Delisser, Patrick; Davidson, Alec J.; Paul, Ketema N.

    2013-01-01

    Shift work and trans-time zone travel lead to insufficient sleep and numerous pathologies. Here, we examined sleep/wake dynamics during chronic exposure to environmental circadian disruption (ECD), and if chronic partial sleep loss associated with ECD influences the induction of shift-related inflammatory disorder. Sleep and wakefulness were telemetrically recorded across three months of ECD, in which the dark-phase of a light-dark cycle was advanced weekly by 6 h. A three month regimen of ECD caused a temporary reorganization of sleep (NREM and REM) and wake processes across each week, resulting in an approximately 10% net loss of sleep each week relative to baseline levels. A separate group of mice were subjected to ECD or a regimen of imposed wakefulness (IW) aimed to mimic sleep amounts under ECD for one month. Fos-immunoreactivity (IR) was quantified in sleep-wake regulatory areas: the nucleus accumbens (NAc), basal forebrain (BF), and medial preoptic area (MnPO). To assess the inflammatory response, trunk blood was treated with lipopolysaccharide (LPS) and subsequent release of IL-6 was measured. Fos-IR was greatest in the NAc, BF, and MnPO of mice subjected to IW. The inflammatory response to LPS was elevated in mice subjected to ECD, but not mice subjected to IW. Thus, the net sleep loss that occurs under ECD is not associated with a pathological immune response. PMID:23696854

  12. Sleep loss and the inflammatory response in mice under chronic environmental circadian disruption.

    PubMed

    Brager, Allison J; Ehlen, J Christopher; Castanon-Cervantes, Oscar; Natarajan, Divya; Delisser, Patrick; Davidson, Alec J; Paul, Ketema N

    2013-01-01

    Shift work and trans-time zone travel lead to insufficient sleep and numerous pathologies. Here, we examined sleep/wake dynamics during chronic exposure to environmental circadian disruption (ECD), and if chronic partial sleep loss associated with ECD influences the induction of shift-related inflammatory disorder. Sleep and wakefulness were telemetrically recorded across three months of ECD, in which the dark-phase of a light-dark cycle was advanced weekly by 6 h. A three month regimen of ECD caused a temporary reorganization of sleep (NREM and REM) and wake processes across each week, resulting in an approximately 10% net loss of sleep each week relative to baseline levels. A separate group of mice were subjected to ECD or a regimen of imposed wakefulness (IW) aimed to mimic sleep amounts under ECD for one month. Fos-immunoreactivity (IR) was quantified in sleep-wake regulatory areas: the nucleus accumbens (NAc), basal forebrain (BF), and medial preoptic area (MnPO). To assess the inflammatory response, trunk blood was treated with lipopolysaccharide (LPS) and subsequent release of IL-6 was measured. Fos-IR was greatest in the NAc, BF, and MnPO of mice subjected to IW. The inflammatory response to LPS was elevated in mice subjected to ECD, but not mice subjected to IW. Thus, the net sleep loss that occurs under ECD is not associated with a pathological immune response. PMID:23696854

  13. Mucin gene 19 (MUC19) expression and response to inflammatory cytokines in middle ear epithelium.

    PubMed

    Kerschner, Joseph E; Khampang, Pawjai; Erbe, Christy B; Kolker, Alexander; Cioffi, Joseph A

    2009-12-01

    Mucin gene 19 (MUC19) has been identified as a major gel-forming mucin in the human middle ear (ME). The objectives of this investigation were to characterize the expression and assess the regulation of MUC19 in the ME cell culture models utilized in the study of otitis media (OM). Findings demonstrate that MUC19 is expressed in both human immortalized cell culture (HMEEC) and chinchilla primary epithelial culture (CMEEC). ME exposure to inflammatory cytokines TNF-alpha, IL-1beta, IL-6 and IL-8 up-regulate MUC19 transcription, most robustly after exposure to TNF-alpha. Kinetic experiments suggest a relative early response in MUC19 transcription and a down-regulation after prolonged exposure. Glycoprotein production was increased in response to the increased transcription as well. Similar to other mucin genes in the ME, MUC19 is differentially regulated after exposure to inflammatory cytokines. The large size, gel-forming properties and up-regulation in response to important inflammatory cytokines of MUC19 suggest that it has significant potential to play a role in both physiology and pathophysiology of the ME. PMID:19533339

  14. ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland.

    PubMed

    Wang, Ching-Shuen; Wee, Yinshen; Yang, Chieh-Hsiang; Melvin, James E; Baker, Olga J

    2016-01-01

    Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A4 and resolvin D1 (RvD1) promotes resolution of inflammation. Our previous in vitro studies indicate that RvD1 activation of ALX/FPR2 resolves cytokine-mediated inflammatory responses in mammalian cells. However, the impact of ALX/FPR2 activation on salivary gland function in vivo is unknown. The objective of this study was to determine whether submandibular glands (SMG) from ALX/FPR2(-/-) mice display enhanced inflammatory responses to lipopolysaccharides (LPS) stimulation. For these studies, C57BL/6 and ALX/FPR2(-/-) mice at age 8-12-week-old were treated with LPS by i.p for 24 h. Salivary gland structure and function were analyzed by histopathological assessment, saliva flow rate, quantitative PCR, Western blot analyses and immunofluorescence. Our results showed the following events in the ALX/FPR2(-/-) mice treated with LPS: a) upregulated inflammatory cytokines and decreased M3R (Muscarinic Acetylcholine receptor M3) and AQP5 (Aquaporin 5) protein expression, b) decreased saliva secretion, c) increased apoptosis, d) alteration of tight junction and neuronal damage. Overall, our data suggest that the loss of ALX/FPR2 results in unresolved acute inflammation and SMG dysfunction (xerostomia) in response to LPS that is similar to human salivary gland dysfunction induced by bacterial infection. PMID:27064029

  15. Leishmania donovani secretory serine protease alters macrophage inflammatory response via COX-2 mediated PGE-2 production.

    PubMed

    Das, Partha; De, Tripti; Chakraborti, Tapati

    2014-12-01

    Leishmania parasites determine the outcome of the infection by inducing inflammatory response that suppresses macrophage's activation. Defense against Leishmania is dependent on Th1 inflammatory response by turning off macrophages' microbicidal property by upregulation of COX-2, as well as immunosuppressive PGE-2 production. To understand the role of L. donovani secretory serine protease (pSP) in these phenomena, pSP was inhibited by its antibody and serine protease inhibitor, aprotinin. Western blot and TAME assay demonstrated that pSP antibody and aprotinin significantly inhibited protease activity in the live Leishmania cells and reduced infection index of L. donovani-infected macrophages. Additionally, ELISA and RT-PCR analysis showed that treatment with pSP antibody or aprotinin hold back COX-2-mediated immunosuppressive PGE-2 secretion with enhancement of Th1 cytokine like IL-12 expression. This was also supported in Griess test and NBT assay, where inhibition of pSP with its inhibitors elevated ROS and NO production. Overall, our study implies the pSP is involved in down-regulation of macrophage microbicidal activity by inducing host inflammatory responses in terms of COX-2-mediated PGE-2 release with diminished reactive oxygen species generation and thus suggests its importance as a novel drug target of visceral leishmaniasis. PMID:25823228

  16. Digibind attenuates cytokine TNFα-induced endothelial inflammatory response: potential benefit role of Digibind in preeclampsia

    PubMed Central

    Wang, Y; Lewis, DF; Adair, CD; Gu, Y; Mason, L; Kipikasa, JH

    2011-01-01

    Objective Exaggerated inflammatory response occurs in preeclampsia. Preeclampsia is also associated with elevated endogenous digoxin-like factors (EDLFs). Clinical data suggest that Digibind (a polyclonal sheep digoxin binding Fab fragment) binds to EDLF and may have the potential to attenuate vasoconstriction and other clinical symptoms of preeclampsia. This study was undertaken to determine if Digibind could attenuate increased endothelial inflammatory response induced by tumor necrosis factor-α (TNFα). Study Design Confluent endothelial cells were treated with TNFα at different concentrations with or without Digibind in culture. Endothelial adhesion molecule ICAM, VCAM and E-selectin expressions were determined by an immunoassay directly detected on the endothelial surface. Effects of Digibind on TNFα-induced extracellular signal-regulated kinase and Na+/K+-ATPase expressions were also examined. Result (1) TNFα induced dose-dependent increases in ICAM, VCAM and E-selectin expressions in endothelial cells; (2) Digibind could attenuate and reduce TNFα-induced upregulation of endothelial E-selectin, ICAM and VCAM expressions. The blocking effect was in a concentration dependent manner; (3) Digibind had no effects on TNFα-induced upregulation of extracellular signal-regulated kinase phosphorylation, but could block TNFα-induced downregulation of Na+/K+-ATPase β1 expression. Conclusion Digibind may exert beneficial effects by preserving cell membrane Na+/K+-ATPase function and consequently to offset increased inflammatory response in endothelial cells. PMID:19148111

  17. Evaluation of inflammatory responses against muscle larvae of different Trichinella species by an image analysis system.

    PubMed

    Bruschi, F; Marucci, G; Pozio, E; Masetti, M

    2009-02-23

    The aim of this study was to evaluate the inflammatory response in the muscle tissue against Trichinella larvae of encapsulated (T. spiralis, T. britovi) and non-encapsulated (T. pseudospiralis) species. The inflammatory response was estimated in histological sections of muscle tissues from Trichinella-infected CD1 mice by a newly developed method. Nuclei were stained with one fluorescent probe, which binds nucleic acids with high affinity, and fluorescence was analysed by a software program. Evaluation of the relative fluorescence units was performed in both peri-capsular (close to the nurse cell-parasite complex) and extra-capsular (where the parasite was not visible) areas. The increase in the number of nuclei in the muscle tissues of Trichinella-infected mice was considered an inflammation marker, since uninfected muscles show low nucleus density. In order to evaluate differences in the nitrosylation pattern between encapsulated (T. spiralis, T. britovi) and non-encapsulated (T. pseudospiralis, Trichinella papuae, Trichinella zimbabwensis) species, L(1) larvae were tested by immunoblotting with an anti-nitrotyrosine polyclonal antibody. Inflammation induced by T. spiralis larvae in muscle tissues is statistically higher than that elicited by the other species, both in peri- and extra-capsular areas. Nitrosylation occurs at a higher level in encapsulated than in non-encapsulated species. The method developed in this work allows demonstration of differences in the host inflammatory response against encapsulated and non-encapsulated Trichinella species. PMID:19046814

  18. Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

    PubMed Central

    Takigawa, Shinya; Chen, Andy; Nishimura, Akinobu; Liu, Shengzhi; Li, Bai-Yan; Sudo, Akihiro; Yokota, Hiroki; Hamamura, Kazunori

    2016-01-01

    Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling. PMID:27164082

  19. Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling.

    PubMed

    Takigawa, Shinya; Chen, Andy; Nishimura, Akinobu; Liu, Shengzhi; Li, Bai-Yan; Sudo, Akihiro; Yokota, Hiroki; Hamamura, Kazunori

    2016-01-01

    Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling. PMID:27164082

  20. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

    PubMed Central

    2012-01-01

    It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers. PMID:22747645

  1. Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

    PubMed

    Cutolo, Maurizio; Seriolo, Bruno; Villaggio, Barbara; Pizzorni, Carmen; Craviotto, Chiara; Sulli, Alberto

    2002-06-01

    Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases. PMID:12114267

  2. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells

    PubMed Central

    Funahashi, Satomi; Okazaki, Yasumasa; Ito, Daiki; Asakawa, Atsushi; Nagai, Hirotaka; Tajima, Masafumi; Toyokuni, Shinya

    2015-01-01

    Asbestos exposure is considered a social burden by causing mesothelioma. Despite the use of synthetic materials, multi-walled carbon nanotubes (MWCNTs) are similar in dimension to asbestos and produce mesothelioma in animals. The role of inflammatory cells in mesothelial carcinogenesis remains unclear. Here, we evaluated the differences in inflammatory cell responses following exposure to these fibrous materials using a luminometer and L-012 (8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutrophils and macrophages, respectively. Crocidolite and amosite induced significant ROS generation by neutrophils with a peak at 10 min, whereas that of chrysotile was ~25% of the crocidolite/amosite response. MWCNTs with different diameters (~15, 50, 115 and 145 nm) and different carcinogenicity did not induce significant ROS in peripheral blood. However, the MWCNTs induced a comparable amount of ROS in RAW264.7 cells to that following asbestos treatment. The peaks for MWCNTs (0.5–1.5 h) were observed earlier than those for asbestos (1–5 h). Apocynin and superoxide dismutase significantly inhibited ROS generation for each fiber, suggesting an involvement of NADPH oxidase and superoxide. Thus, asbestos and MWCNTs induce different oxidative responses in inflammatory cells, indicating the importance of mesothelial cell evaluation for carcinogenesis. PMID:25759516

  3. Oleuropein suppresses LPS-induced inflammatory responses in RAW 264.7 cell and zebrafish.

    PubMed

    Ryu, Su-Jung; Choi, Hyeon-Son; Yoon, Kye-Yoon; Lee, Ok-Hwan; Kim, Kui-Jin; Lee, Boo-Yong

    2015-02-25

    Oleuropein is one of the primary phenolic compounds present in olive leaf. In this study, the anti-inflammatory effect of oleuropein was investigated using lipopolysaccharide (LPS)-stimulated RAW 264.7 and a zebrafish model. The inhibitory effect of oleuropein on LPS-induced NO production in macrophages was supported by the suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, our enzyme immunoassay showed that oleuropein suppressed the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6). Oleuropein inhibited the translocation of p65 by suppressing phosphorylation of inhibitory kappa B-α (IκB-α). Oleuropein also decreased activation of ERK1/2 and JNK, which are associated with LPS-induced inflammation, and its downstream gene of AP-1. Furthermore, oleuropein inhibited LPS-stimulated NO generation in a zebrafish model. Taken together, our results demonstrated that oleuropein could reduce inflammatory responses by inhibiting TLR and MAPK signaling, and may be used as an anti-inflammatory agent. PMID:25613688

  4. Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge

    PubMed Central

    Qin, Xiangyang; Jiang, Xinru; Jiang, Xin; Wang, Yuli; Miao, Zhulei; He, Weigang; Yang, Guizhen; Lv, Zhenhui; Yu, Yizhi; Zheng, Yuejuan

    2016-01-01

    Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria)-mediated production of cytokines (IL-6, TNF-α, MCP-1, etc) in Raw264.7 cells, primary macrophages, dendritic cells and human monocytes. MCL plays an anti-inflammatory role by inhibiting LPS-induced activation of NF-κB and PI3K/Akt/p70S6K pathways. It has negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. In the acute peritonitis mouse model, MCL reduced the secretion of IL-6, TNF-α, IL-1β, MCP-1, IFN-β and IL-10 in sera, and ameliorated lung and liver damage. MCL down-regulated the high mortality rate caused by lethal LPS challenge. Collectively, our data illustrated that MCL enabled maintenance of immune equilibrium may represent a potentially new anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock. PMID:26984741

  5. The monoacylglycerol lipase inhibitor JZL184 decreases inflammatory response in skeletal muscle contusion in rats.

    PubMed

    Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Wang, Meng; Zhao, Rui; Wang, Lin-Lin; Li, Shan-Shan; Liu, Min; Li, Jiao-Yong; Zhang, Meng-Zhou; Guan, Da-Wei

    2015-08-15

    Muscle wound healing process is a typical inflammation-evoked event. The monoacylglycerol lipase (MAGL) inhibitor (4-nitrophenyl)4-[bis(1,3-benzodioxol -5-yl)-hydroxymethyl]piperidine-1-carboxylate (JZL184) has been previously reported to reduce inflammation in colitis and acute lung injury in mice, which provide a new strategy for primary care of skeletal muscle injury. We investigated the effect of JZL184 on inflammation in rat muscle contusion model, and found decreased neutrophil and macrophage infiltration and pro-inflammatory cytokine expression. With extension of post-traumatic interval, myofiber regeneration was significantly hindered with increased collagen types I and ІІІ mRNAfibroblast infiltration as well as promoted fibrosis. Furthermore, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-morpholin-4-ylpyrazole-3-carboxamide (AM281, a selective cannabinoid CB1 receptor antagonist) and [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630, a selective cannabinoid CB2 receptor antagonist) treatment alleviated the anti-inflammatory effect of JZL184. Our findings demonstrate that JZL184 is able to inhibit the inflammatory response and interfere with contused muscle healing, in which the anti-inflammatory action may be mediated through cannabinoid CB1 and CB2 receptors. PMID:25912803

  6. Astragalus polysaccharide reduces inflammatory response by decreasing permeability of LPS-infected Caco2 cells.

    PubMed

    Wang, Xiaofei; Li, Yulong; Yang, Xiaojun; Yao, Junhu

    2013-10-01

    As the major constituent of Radix Astragali, Astragalus polysaccharide (APS) is known for its anti-inflammation and immunomodulatory functions. The objective of this study was to investigate the effect of APS on inflammatory response and structural changes in lipopolysaccharide (LPS)-infected Caco2 cells. Caco2 cells were co-cultured with APS and LPS, with APS added after the addition of LPS (post-addition), before the addition of LPS (pre-addition), or simultaneously with the addition of LPS (simultaneous addition). The mRNA expression of inflammatory indicators and tight junctions was measured by RT-qPCR. Short circuit current (Isc) was recorded by an Ussing chamber system. Addition of APS significantly down-regulated the expression of TNF-α, IL-1β and IL-8 (P<0.05) and the Isc levels (P<0.05) of LPS-infected Caco2 cells for all three administration treatments. The minimum anti-inflammatory concentration of APS was 50, 100, and 100 μg/mL for pre-, post-, and simultaneous additions of APS, respectively. The mRNA expression of zonula occludens-1 (ZO-1) and occludin was significantly up-regulated for post- and pre-additions of APS, respectively (P<0.05). Results suggested that APS had anti-inflammatory and structure protective properties for LPS-infected Caco2 cells, and may be used as a preventative treatment for intestine cells. PMID:23916649

  7. Phytoncide Extracted from Pinecone Decreases LPS-Induced Inflammatory Responses in Bovine Mammary Epithelial Cells.

    PubMed

    Kang, Sukyung; Lee, Jae Sung; Lee, Hai Chon; Petriello, Michael C; Kim, Bae Yong; Do, Jeong Tae; Lim, Dae-Seog; Lee, Hong Gu; Han, Sung Gu

    2016-03-28

    Mastitis is a prevalent inflammatory disease that remains one of the main causes of poor quality of milk. Phytoncides are naturally occurring anti-inflammatory compounds derived from plants and trees. To determine if treatment with phytoncide could decrease the severity of lipopolysaccharide (LPS)-induced inflammatory responses, mammary alveolar epithelial cells (MAC-T) were pretreated with phytoncide (0.02% and 0.04% (v/v)) followed by LPS treatment (1 and 25 μg/ml). The results demonstrated that phytoncide downregulated LPSinduced pro-inflammatory cyclooxygenase-2 (COX-2) expression. Additionally, LPS-induced activation of ERK1/2, p38, and Akt was attenuated by phytoncide. Treatment of cells with known pharmacological inhibitors of ERK1/2 (PD98059), p38 (SB203580), and Akt (LY294002) confirmed the association of these signaling pathways with the observed alterations in COX-2 expression. Moreover, phytoncide attenuated LPS-induced NF-κB activation and superoxide production, and, finally, treatment with phytoncide increased Nrf2 activation. Results suggest that phytoncide can decrease LPS-induced inflammation in MAC-T cells. PMID:26608166

  8. Francisella Infection in Cultured Tilapia in Thailand and the Inflammatory Cytokine Response.

    PubMed

    Jantrakajorn, Sasibha; Wongtavatchai, Janenuj

    2016-06-01

    Francisella infections developed in freshwater Nile Tilapia Oreochromis niloticus and red tilapia Oreochromis spp. farms in Thailand during 2012-2014. The diseased fish were lethargic and pale in color and showed numerous white nodules in their enlarged spleens. Histopathological examination and electron microscopy suggested that the white nodules were multifocal granulomas consisting of coccobacilli within vacuolated cells. Isolation of Francisella-like bacteria was achieved from 42 of 100 samples, while polymerase chain reaction confirmed Francisella infections in all samples. Analysis of the 16S rRNA gene from samples obtained from three different geographical culture areas revealed more than 99% similarity with F. noatunensis subsp. orientalis. The influence of Francisella infection on inflammatory cytokines was determined on splenic cells of fish intraperitoneally injected with the bacteria (0.8 × 10(5) colony-forming units per fish). Infected tilapia showed significantly greater expression of the pro-inflammatory genes interleukin-1β (IL-1β) and tumor necrotic factor-α (TNF-α) within 24 h postinjection (hpi) and for up to 96 hpi. However, down-regulation of an anti-inflammatory gene, transforming growth factor-β (TGF-β) was observed as early as 24 hpi. This investigation demonstrates that an imbalance between pro- and anti-inflammatory cytokines in response to the infection may account for the substantial number of granulomas in fish hematopoietic tissues that was found in the later stage of the disease. Received September 9, 2015; accepted December 13, 2015. PMID:27196982

  9. Systemic Inflammatory Response to Smoking in Chronic Obstructive Pulmonary Disease: Evidence of a Gender Effect

    PubMed Central

    Cruz, Tamara; Kalko, Susana Graciela; Agustí, Alvar

    2014-01-01

    Background Tobacco smoking is the main risk factor of chronic obstructive pulmonary disease (COPD) but not all smokers develop the disease. An abnormal pulmonary and systemic inflammatory response to smoking is thought to play a major pathogenic role in COPD, but this has never been tested directly. Methods We studied the systemic biomarker and leukocyte transcriptomic response (Affymetrix microarrays) to smoking exposure in 10 smokers with COPD and 10 smokers with normal spirometry. We also studied 10 healthy never smokers (not exposed to smoking) as controls. Because some aspects of COPD may differ in males and females, and the inflammatory response to other stressors (infection) might be different in man and women, we stratified participant recruitment by sex. Differentially expressed genes were validated by q-PCR. Ontology enrichment was evaluated and interaction networks inferred. Results Principal component analysis identified sex differences in the leukocyte transcriptomic response to acute smoking. In both genders, we identified genes that were differentially expressed in response to smoking exclusively in COPD patients (COPD related signature) or smokers with normal spirometry (Smoking related signature), their ontologies and interaction networks. Conclusions The use of an experimental intervention (smoking exposure) to investigate the transcriptomic response of peripheral leukocytes in COPD is a step beyond the standard case-control transcriptomic profiling carried out so far, and has facilitated the identification of novel COPD and Smoking expression related signatures which differ in males and females. PMID:24830457

  10. Immune/Inflammatory Response and Hypocontractility of Rabbit Colonic Smooth Muscle After TNBS-Induced Colitis

    PubMed Central

    Zhang, Yonggang; Li, Fang; Wang, Hong; Yin, Chaoran; Huang, JieAn; Mahavadi, Sunila; Murthy, Karnam S.

    2016-01-01

    Background The contractility of colonic smooth muscle is dysregulated due to immune/inflammatory responses in inflammatory bowel diseases. Inflammation in vitro induces up-regulation of regulator of G-protein signaling 4 (RGS4) expression in colonic smooth muscle cells. Aims To characterize the immune/inflammatory responses and RGS4 expression pattern in colonic smooth muscle after induction of colitis. Methods Colitis was induced in rabbits by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Innate/adaptive immune response RT-qPCR array was performed using colonic circular muscle strips. At 1–9 weeks after colonic intramuscular microinjection of lentivirus, the distal and proximal colons were collected, and muscle strips and dispersed muscle cells were prepared from circular muscle layer. Expression levels of RGS4 and NFκB signaling components were determined by Western blot analysis. The biological consequences of RGS4 knockdown were assessed by measurement of muscle contraction and phospholipase C (PLC)-β activity in response to acetylcholine (ACh). Results Contraction in response to ACh was significantly inhibited in the inflamed colonic circular smooth muscle cells. RGS4, IL-1, IL-6, IL-8, CCL3, CD1D, and ITGB2 were significantly up-regulated, while IL-18, CXCR4, CD86, and C3 were significantly down-regulated in the inflamed muscle strips. RGS4 protein expression in the inflamed smooth muscles was dramatically increased. RGS4 stable knockdown in vivo augmented ACh-stimulated PLC-β activity and contraction in colonic smooth muscle cells. Conclusion Inflamed smooth muscle exhibits up-regulation of IL-1-related signaling components, Th1 cytokines and RGS4, and inhibition of contraction. Stable knockdown of endogenous RGS4 in colonic smooth muscle increases PLC-β activity and contractile responses. PMID:26879904

  11. Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model

    PubMed Central

    Lever, Amanda R; Park, Hyoungshin; Mulhern, Thomas J; Jackson, George R; Comolli, James C; Borenstein, Jeffrey T; Hayden, Patrick J; Prantil-Baun, Rachelle

    2015-01-01

    Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner. PMID:25847914

  12. Acinar inflammatory response to lipid derivatives generated in necrotic fat during acute pancreatitis.

    PubMed

    Mateu, A; Ramudo, L; Manso, M A; Closa, D; De Dios, I

    2014-09-01

    Lipids play a role in acute pancreatitis (AP) progression. We investigate the ability of pancreatic acinar cells to trigger inflammatory response in the presence of lipid compounds generated in necrotic areas of peripancreatic adipose tissue (AT) during AP induced in rats by 5% sodium taurocholate. Lipid composition of AT was analyzed by HPLC-mass spectrometry. Acinar inflammatory response to total lipids as well as to either the free fatty acid (FFA) fraction or their chlorinated products (Cl-FFAs) was evaluated. For this, mRNA expression of chemokine (C-C motif) ligand 2 (CCL2) and P-selectin as well as the activation of MAPKs, NF-κB and STAT-3 were analyzed in pancreatic acini. Myeloperoxidase (MPO) activity, as an inducer of Cl-FFA generation, was also analyzed in AT. MPO activity significantly increased in necrotic (AT-N) induced changes in lipid composition of necrotic fat, such as increase in FFA and phospholipid (PL) content, generation of Cl-FFAs and increases in saturated FFAs and in the poly-:mono-unsaturated FFA ratio. Total lipids from AT-N induced overexpression of CCL2 and P-selectin in pancreatic acini as well as MAPKs phosphorylation and activation of NF-κB and STAT3. FFAs, but not Cl-FFAs, up-regulated CCL2 and P-selectin in acinar cells. We conclude that FFAs are capable of up-regulating inflammatory mediators in pancreatic acini and given that they are highly produced during AP, mainly may contribute to the inflammatory response triggered in acinar cells by fat necrosis. No role is played by Cl-FFAs generated as a result of neutrophil infiltration. PMID:24959971

  13. The hemic response of white-spotted bamboo sharks (Chiloscyllium plagiosum) with inflammatory disease.

    PubMed

    Alexander, Amy B; Parkinson, Lily A; Grant, Krystan R; Carlson, Eric; Campbell, Terry W

    2016-05-01

    As elasmobranch medicine becomes more commonplace, there continues to be confusion with techniques and evaluation of the shark hemogram and it remains unknown if they are able to mount an inflammatory hemic response. The aims of this study were to compare two total white blood cell (WBC) count techniques, establish a reference interval for captive white-spotted bamboo sharks (Chiloscyllium plagiosum), and determine if elasmobranchs are capable of mounting an inflammatory hemic response. Correlation statistics were performed on hematologic results for healthy female bamboo sharks to assess the use of Natt-Herrick's and phloxine methods. Total WBC counts and differentials were obtained from males with severe traumatic clasper wounds and compared to the healthy females. We elected clasper amputation as the preferred treatment intervention and post-operative hematology was performed one month later. There was poor correlation of leukocyte counts between the two WBC count methods. Hematologic values were established for the females and males pre- and post-operatively. Males with wounds had a marked leukocytosis and heterophilia. Post-operative blood work showed a resolution of total WBC count and a trend toward resolution of the heterophilia. This study provides hematologic values for white-spotted bamboo sharks and confirms that the Natt-Herrick's method is preferred for lymphocytic species. Hematologic differences present in males with clasper wounds suggests that elasmobranchs do mount an inflammatory hemic response. Treatment via clasper amputation proved to be a safe and efficient means for clinical treatment that led to a trend toward resolution of the inflammatory leukogram. Zoo Biol. 35:251-259, 2016. © 2016 Wiley Periodicals, Inc. PMID:26970476

  14. Histamine release and fibrinogen adsorption mediate acute inflammatory responses to biomaterial implants in humans

    PubMed Central

    Zdolsek, Johann; Eaton, John W; Tang, Liping

    2007-01-01

    Background Medical implants often fail as a result of so-called foreign body reactions during which inflammatory cells are recruited to implant surfaces. Despite the clinical importance of this phenomenon, the mechanisms involved in these reactions to biomedical implants in humans are not well understood. The results from animal studies suggest that both fibrinogen adsorption to the implant surface and histamine release by local mast cells are involved in biomaterial-mediated acute inflammatory responses. The purpose of this study was to test this hypothesis in humans. Methods Thirteen male medical student volunteers (Caucasian, 21–30 years of age) were employed for this study. To assess the importance of fibrinogen adsorption, six volunteers were implanted with polyethylene teraphthalate disks pre-coated with their own (fibrinogen-containing) plasma or (fibrinogen-free) serum. To evaluate the importance of histamine, seven volunteers were implanted with uncoated disks with or without prior oral administration of histamine receptor antagonists. The acute inflammatory response was estimated 24 hours later by measuring the activities of implant-associated phagocyte-specific enzymes. Results Plasma coated implants accumulated significantly more phagocytes than did serum coated implants and the recruited cells were predominantly macrophage/monocytes. Administration of both H1 and H2 histamine receptor antagonists greatly reduced the recruitment of macrophages/monocytes and neutrophils on implant surfaces. Conclusion In humans – as in rodents – biomaterial-mediated inflammatory responses involve at least two crucial events: histamine-mediated phagocyte recruitment and phagocyte accumulation on implant surfaces engendered by spontaneously adsorbed host fibrinogen. Based on these results, we conclude that reducing fibrinogen:surface interactions should enhance biocompatibility and that administration of histamine receptor antagonists prior to, and shortly after

  15. Biaryl amide compounds reduce the inflammatory response in macrophages by regulating Dectin-1.

    PubMed

    Hyung, Kyeong Eun; Lee, Mi Ji; Lee, Yun-Jung; Lee, Do Ik; Min, Hye Young; Park, So-Young; Min, Kyung Hoon; Hwang, Kwang Woo

    2016-03-01

    Macrophages are archetypal innate immune cells that play crucial roles in the recognition and phagocytosis of invading pathogens, which they identify using pattern recognition receptors (PRRs). Dectin-1 is essential for antifungal immune responses, recognizing the fungal cellular component β-glucan, and its role as a PRR has been of increasing interest. Previously, we discovered and characterized a novel biaryl amide compound, MPS 03, capable of inhibiting macrophage phagocytosis of zymosan. Therefore, in this study we aimed to identify other biaryl amide compounds with greater effectiveness than MPS 03, and elucidate their cellular mechanisms. Several MPS 03 derivatives were screened, four of which reduced zymosan phagocytosis in a similar manner to MPS 03. To establish whether such phagocytosis inhibition influenced the production of inflammatory mediators, pro-inflammatory cytokine and nitric oxide (NO) levels were measured. The production of TNF-α, IL-6, IL-12, and NO was significantly reduced in a dose-dependent manner. Moreover, the inflammation-associated MAPK signaling pathway was also affected by biaryl amide compounds. To investigate the underlying cellular mechanism, PRR expression was measured. MPS 03 and its derivatives were found to inhibit zymosan phagocytosis by decreasing Dectin-1 expression. Furthermore, when macrophages were stimulated by zymosan after pretreatment with biaryl amide compounds, downstream transcription factors such as NFAT, AP-1, and NF-κB were downregulated. In conclusion, biaryl amide compounds reduce zymosan-induced inflammatory responses by downregulating Dectin-1 expression. Therefore, such compounds could be used to inhibit Dectin-1 in immunological experiments and possibly regulate excessive inflammatory responses. PMID:26828762

  16. Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma.

    PubMed

    Reghini, Maria Fernanda S; Ramires Neto, Carlos; Segabinazzi, Lorenzo G; Castro Chaves, Maria Manoela B; Dell'Aqua, Camila de Paula F; Bussiere, Maria Clara C; Dell'Aqua, José Antonio; Papa, Frederico O; Alvarenga, Marco Antonio

    2016-07-15

    Degenerative changes of the endometrium are directly related to age and fertility in mares. Chronic degenerative endometritis (CDE) is correlated with uterine fluid retention and reduced ability to clear uterine inflammation. Recent research in the areas of equine surgery and sports medicine has shown that platelet-rich plasma (PRP) treatment acts as an immunomodulator of the inflammatory response. Therefore, the aim of this study was to determine if the uterine infusion of PRP could modulate the local inflammatory response and modify the intrauterine NO concentrations after artificial insemination (AI) in both normal mares and those with CDE. Thirteen mares with endometrium classified as grade III on the histology (mares with CDE) and eight mares with endometrial histological classification I or II-a normal mares were selected to investigate the effect of PRP therapy. The mares were inseminated with fresh semen in two consecutive cycles in a crossover study design. Thereby, each mare served as its own control and the treatment was performed with intrauterine PRP infusion four hours after AI. The percentage of neutrophils in uterine cytology (CIT, %), uterine fluid accumulation observed on ultrasonography (FLU, mm) and nitric oxide concentration of uterine fluid (NO, μM) were analyzed before and 24 hours after AI. The results reported that mares with CDE (CIT, 68.3 ± 3.27, FLU, 10.7 ± 1.61) have a higher (P < 0.05) intrauterine inflammatory response after AI than normal mares (CIT, 24.4 ± 3.56, FLU, 0), but NO concentrations did not differ (P > 0.05) between categories of mares. In treated cycles with PRP, the intrauterine inflammatory response decrease (P < 0.05) in CDE mares (CDE: CIT, 31.4 ± 6.48, FLU, 5.5 ± 1.28; normal mares: CIT, 13.5 ± 4.31, FLU, 0) when compared with nontreated cycle (CDE: CIT, 68.3 ± 3.27, FLU, 10.7 ± 1.61; NM: CIT, 24.4 ± 3.56, FLU, 0), but did not modify NO concentrations in uterine fluid. Thus, we can

  17. Response and habituation of pro and anti inflammatory gene expression to repeated acute stress

    PubMed Central

    McInnis, Christine M.; Wang, Diana; Gianferante, Danielle; Hanlin, Luke; Chen, Xuejie; Thoma, Myriam V.; Rohleder, Nicolas

    2015-01-01

    Introduction Acute stress induces increases in plasma inflammatory mediators, which do not habituate to repeated stress. Inflammation is a risk factor for age-related illnesses, highlighting the need to understand factors controlling inflammation. No studies have examined changes in pro- and anti-inflammatory gene expression in response to repeated acute stress in humans. Methods RNA was isolated from peripheral blood before, 30 and 120 minutes after exposure of n=32 healthy human participants to the Trier Social Stress Test (TSST) on two days. Gene expression of interleukin (IL)-6, IL-1β, nuclear factor (NF)-κB and IκB was measured repeatedly on both days. We further assessed leukocyte numbers, plasma IL-6, and salivary cortisol. Results Stress induced IL-6 (F=44.7; p<0.001) and cortisol responses (F=18.6; p<0.001). Cortisol responses habituated (F=5.1, p=0.003), but IL-6 responses did not (n.s.). All genes increased in response to initial stress (IL-6: F=3.8; p=0.029; IL-1β: F=7.1; p=0.008; NF-κB: F=5.1; p=0.009; IκB; F=4.7; p=0.013) and showed habituation to repeated stress (IL-6: t=2.3; p=0.03; IL-1β: t=3.9; p=0.001; NF-κB: t=2.1; p=0.041; IκB: t=3.1; p=0.005). Day 1 responses of IL-1β and IκB were not explained by changes in leukocyte populations, but IL-6 and NF-κB, as well as most day 2 changes were not independent of leukocyte populations. Conclusions Stress response and habituation of pro- and anti-inflammatory gene expression as found here might indicate that even on an intracellular level, inflammatory responses to acute stress are adaptive in that they respond to initial, but habituate to repeated, similar stress. Future studies will need to test whether non-habituation is predictive of disease. PMID:25683696

  18. Tetrandrine suppresses articular inflammatory response by inhibiting pro-inflammatory factors via NF-κB inactivation.

    PubMed

    Gao, Li-Na; Feng, Qi-Shuai; Zhang, Xin-Fang; Wang, Qiang-Song; Cui, Yuan-Lu

    2016-09-01

    Targeting activated macrophages using anti-inflammatory phytopharmaceuticals has been proposed as general therapeutic approaches for rheumatic diseases. Besides macrophages, chondrocytes are another promising target of anti-inflammatory agents. Tetrandrine is a major bisbenzylisoquinoline alkaloid isolated from Stephania tetrandrae S. Moore which has been used for 2,000 years as an antirheumatic herbal drug in China. Although, the anti-inflammatory effect of tetrandrine has been demonstrated, the mechanism has not been clearly clarified. In this study, we designed a comprehensive anti-inflammatory evaluation system for tetrandrine, including complete Freund's adjuvant (CFA)-induced arthritis rat, LPS-induced macrophage RAW 264.7 cells, and chondrogenic ATDC5 cells. The results showed that tetrandrine alleviated CFA-induced foot swelling, synovial inflammation, and pro-inflammatory cytokines secretion. Tetrandrine could inhibit IL-6, IL-1β, and TNF-α expression via blocking the nuclear translocation of nuclear factor (NF)-κB p65 in LPS-induced RAW 264.7 cells. Moreover, ATDC5 cells well responded to LPS induced pro-inflammatory mediators secretion and tissue degradation, and tetrandrine could also inhibit the production of nitric oxide and prostaglandin E2 , as well as the expression of matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 via inhibiting IκBα phosphorylation and degradation. In conclusion, the results showed that one of the anti-inflammatory mechanisms of tetrandrine was inhibiting IκBα and NF-κB p65 phosphorylation in LPS-induced macrophage RAW 264.7 cells and chondrogenic ATDC5 cells. Moreover, we introduce a vigorous in vitro cell screening system, LPS-induced murine macrophage RAW 264.7 cells coupling chondrogenic ADTC5 cells, for screening anti-rheumatic drugs. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1557-1568, 2016. PMID:26748661

  19. Effects of resveratrol on the treatment of inflammatory response induced by severe burn.

    PubMed

    Tao, Ke; Bai, Xiaozhi; Jia, Wenbin; Liu, Yang; Zhu, Xiongxiang; Han, Juntao; Dong, Maolong; Li, Jun; Chen, Dongdong; Hu, Dahai

    2015-01-01

    The aim of this study was to preliminarily investigate the effects of resveratrol on the treatment of systemic inflammatory response induced by severe burn wounding. Through the simulation experiment in vivo on burned mice and simulative experiment in vitro on mice macrophage respectively, differences of the related pro-inflammatory cytokines and SIRT1 expression levels between the resveratrol-treated group and the untreated control group were detected and analyzed. The results of the simulation experiment in vivo on burned mice manifested that the survival rate of the mice in the resveratrol-treated group was markedly higher than that of controls (p<0.05). Resveratrol could significantly reduce the levels of pro-inflammatory factors TNF-α, IL-1β, and IL-6 in serum (p<0.01) and greatly elevate the expression level of SIRT1 (p<0.01). The results of the simulative experiment in vitro on mice macrophage showed no significant difference in TNF-α, IL-1β, or IL-6 contents among three groups (C, mice macrophage control group; R, resveratrol-treated macrophage group; I, SIRT1-inhibitor-treated macrophage group). Whereas, after lipopolysaccharide (LPS) activation (L group), macrophage TNF-α, IL-1β, and IL-6 levels were significantly increased in L group, dramatically higher than those in L+R group (LPS and resveratrol treatment group) (p<0.01). After adding SITR1 inhibitor, three pro-inflammatory cytokines in L+R+I group all showed significant increases compared with those in L+R group (p<0.01). LPS activated macrophages were able to promote the expression of pro-inflammatory cytokines. By upregulating the expression levels of SIRT1, resveratrol could effectively inhibit the inflammation cascade reaction and increase the survival rate of severe burn with bacterial infections in a large extent. PMID:25586484

  20. Inflammatory cytokines and plasma redox status responses in hypertensive subjects after heat exposure

    PubMed Central

    Fonseca, S.F.; Mendonça, V.A.; Teles, M.C.; Ribeiro, V.G.C.; Tossige-Gomes, R.; Neves, C.D.C.; Rocha-Vieira, E.; Leite, L.H.R.; Soares, D.D.; Coimbra, C.C.; Lacerda, A.C.R.

    2016-01-01

    Hypertension is characterized by a pro-inflammatory status, including redox imbalance and increased levels of pro-inflammatory cytokines, which may be exacerbated after heat exposure. However, the effects of heat exposure, specifically in individuals with inflammatory chronic diseases such as hypertension, are complex and not well understood. This study compared the effects of heat exposure on plasma cytokine levels and redox status parameters in 8 hypertensive (H) and 8 normotensive (N) subjects (age: 46.5±1.3 and 45.6±1.4 years old, body mass index: 25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure: 98.0±2.8 and 86.0±2.3 mmHg, respectively). They remained at rest in a sitting position for 10 min in a thermoneutral environment (22°C) followed by 30 min in a heated environmental chamber (38°C and 60% relative humidity). Blood samples were collected before and after heat exposure. Plasma cytokine levels were measured using sandwich ELISA kits. Plasma redox status was determined by thiobarbituric acid reactive substances (TBARS) levels and ferric reducing ability of plasma (FRAP). Hypertensive subjects showed higher plasma levels of IL-10 at baseline (P<0.05), although levels of this cytokine were similar between groups after heat exposure. Moreover, after heat exposure, hypertensive individuals showed higher plasma levels of soluble TNF receptor (sTNFR1) and lower TBARS (P<0.01) and FRAP (P<0.05) levels. Controlled hypertensive subjects, who use angiotensin-converting-enzyme inhibitor (ACE inhibitors), present an anti-inflammatory status and balanced redox status. Nevertheless, exposure to a heat stress condition seems to cause an imbalance in the redox status and an unregulated inflammatory response. PMID:26840715

  1. 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

  2. Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response

    PubMed Central

    Santiago, Felix W.; Halsey, Eric S.; Siles, Crystyan; Vilcarromero, Stalin; Guevara, Carolina; Silvas, Jesus A.; Ramal, Cesar; Ampuero, Julia S.; Aguilar, Patricia V.

    2015-01-01

    Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen. PMID:26496497

  3. Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response.

    PubMed

    Santiago, Felix W; Halsey, Eric S; Siles, Crystyan; Vilcarromero, Stalin; Guevara, Carolina; Silvas, Jesus A; Ramal, Cesar; Ampuero, Julia S; Aguilar, Patricia V

    2015-01-01

    Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen. PMID:26496497

  4. Resistance training, visceral obesity and inflammatory response: a review of the evidence.

    PubMed

    Strasser, B; Arvandi, M; Siebert, U

    2012-07-01

    Intra-abdominal obesity is an important risk factor for low-grade inflammation, which is associated with increased risk for diabetes mellitus and cardiovascular disease. For the most part, recommendations to treat or prevent overweight and obesity via physical activity have focused on aerobic endurance training as it is clear that aerobic training is associated with much greater energy expenditure during the exercise session than resistance training. However, due to the metabolic consequences of reduced muscle mass, it is understood that normal ageing and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. Whether resistance training alters visceral fat and the levels of several pro-inflammatory cytokines produced in adipose tissue has not been addressed in earlier reviews. Because evidence suggests that resistance training may promote a negative energy balance and may change body fat distribution, it is possible that an increase in muscle mass after resistance training may be a key mediator leading to a better metabolic control. Considering the benefits of resistance training on visceral fat and inflammatory response, an important question is: how much resistance training is needed to confer such benefits? Therefore, the purpose of this review was to address the importance of resistance training on abdominal obesity, visceral fat and inflammatory response. PMID:22385646

  5. Inflammatory Response Using Different Lipid Parenteral Nutrition Formulas in Children After Hematopoietic Stem Cell Transplantation.

    PubMed

    Baena-Gómez, María Auxiliadora; de la Torre-Aguilar, María José; Aguilera-García, Concepción María; Olza, Josune; Pérez-Navero, Juan Luis; Gil-Campos, Mercedes

    2016-07-01

    Nutritional support is an integral part of the supportive care of hematopoietic stem cell transplantation (HSCT) patients. Omega-3 fatty acids (n-3 FA) emulsions in parenteral nutrition (PN) may modify the inflammatory response. The purpose of this study is to compare plasma cytokine levels in children after HSCT using an n-3 FA-containing lipid emulsion (LE) and a soybean oil-based formulation in PN. A randomized double-blind controlled trial was conducted on 14 children following HSCT. Children were randomized to receive either a fish oil or a soybean oil LE. Blood samples were drawn at baseline, on Day 10 and after completion of PN to analyze plasma interleukin 1 beta (IL-1β), 2 (IL-2), 6 (IL-6), 8 (IL-8), 10 (IL-10), and tumor necrosis factor alpha (TNF-α). After 10 days of PN, there were no significant changes in interleukins levels when comparing the two groups or time points (baseline vs. Day 10 of PN). In children requiring PN >21 days, IL-10 and TNF-α levels (P ≤ 0.05) were lower in the fish-oil-containing LE group. Fish oil- and soybean oil-supplemented PN administered for at least 10 days does not cause inflammatory changes. Prolonged PN based on fish oil LE may modulate the inflammatory response. PMID:27270245

  6. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study

    PubMed Central

    Kaspar, Felix; Jelinek, Herbert F.; Perkins, Steven; Al-Aubaidy, Hayder A.; deJong, Bev; Butkowski, Eugene

    2016-01-01

    Objective. This study compared acute and late effect of single-bout endurance training (ET) and high-intensity interval training (HIIT) on the plasma levels of four inflammatory cytokines and C-reactive protein and insulin-like growth factor 1. Design. Cohort study with repeated-measures design. Methods. Seven healthy untrained volunteers completed a single bout of ET and HIIT on a cycle ergometer. ET and HIIT sessions were held in random order and at least 7 days apart. Blood was drawn before the interventions and 30 min and 2 days after the training sessions. Plasma samples were analyzed with ELISA for the interleukins (IL), IL-1β, IL-6, and IL-10, monocyte chemoattractant protein-1 (MCP-1), insulin growth factor 1 (IGF-1), and C-reactive protein (CRP). Statistical analysis was with Wilcoxon signed-rank tests. Results. ET led to both a significant acute and long-term inflammatory response with a significant decrease at 30 minutes after exercise in the IL-6/IL-10 ratio (−20%; p = 0.047) and a decrease of MCP-1 (−17.9%; p = 0.03). Conclusion. This study demonstrates that ET affects the inflammatory response more adversely at 30 minutes after exercise compared to HIIT. However, this is compensated by a significant decrease in MCP-1 at two days associated with a reduced risk of atherosclerosis. PMID:27212809

  7. Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice

    PubMed Central

    Fiume, Giuseppe; Scialdone, Annarita; Albano, Francesco; Rossi, Annalisa; Maria Tuccillo, Franca; Rea, Domenica; Palmieri, Camillo; Caiazzo, Elisabetta; Cicala, Carla; Bellevicine, Claudio; Falcone, Cristina; Vecchio, Eleonora; Pisano, Antonio; Ceglia, Simona; Mimmi, Selena; Iaccino, Enrico; Laurentiis, Annamaria de; Pontoriero, Marilena; Agosti, Valter; Troncone, Giancarlo; Mignogna, Chiara; Palma, Giuseppe; Arra, Claudio; Mallardo, Massimo; Maria Buonaguro, Franco; Scala, Giuseppe; Quinto, Ileana

    2015-01-01

    Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4+ and CD8+ T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation. PMID:26343909

  8. CRAM-A indicates IFN-γ-associated inflammatory response in breast cancer.

    PubMed

    Sarmadi, Parisa; Tunali, Gurcan; Esendagli-Yilmaz, Guldal; Yilmaz, Kerim Bora; Esendagli, Gunes

    2015-12-01

    Atypical chemokine receptors (ACKRs) function as endpoint regulators of chemokine gradients. These non-signaling receptors that are transiently expressed under inflammatory conditions have critical roles in the control or maintenance of immune responses. Alternatively, here, CCRL2 (ACKR5) expression was determined to be constitutive in breast cancer cells. Increased amount of CCRL2 was also found in breast tumor tissues with high immune infiltration. Its expression was upregulated in the presence of pro-inflammatory cytokines, IL-1β, TNF-α, IL-6, and especially IFN-γ⋅ Moreover, an alternative transcript of CCRL2 gene, CRAM-A, was specifically expressed in a transient fashion under the influence of IFN-γ. CRAM-A expression was also positively correlated with the presence of IFN-γ mRNA in patient samples. CCRL2-associated chemotactic molecules, chemerin, CCL19 and CCL5, were also detected in cancer tissues and CCL5 mRNA level was correlated with that of CRAM-A and IFN-γ. Hence, in breast cancer, CRAM-A becomes specifically upregulated under inflammatory stimuli and may serve as a potential marker of immune response. PMID:26563945

  9. CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis

    PubMed Central

    Castoldi, Angela; Amano, Mariane Tami; Nunes, Valeria Sutti; Quintao, Eder Carlos Rocha; Cazita, Patrícia Miralda

    2016-01-01

    Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases. PMID:27293313

  10. Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice.

    PubMed

    Fiume, Giuseppe; Scialdone, Annarita; Albano, Francesco; Rossi, Annalisa; Tuccillo, Franca Maria; Rea, Domenica; Palmieri, Camillo; Caiazzo, Elisabetta; Cicala, Carla; Bellevicine, Claudio; Falcone, Cristina; Vecchio, Eleonora; Pisano, Antonio; Ceglia, Simona; Mimmi, Selena; Iaccino, Enrico; de Laurentiis, Annamaria; Pontoriero, Marilena; Agosti, Valter; Troncone, Giancarlo; Mignogna, Chiara; Palma, Giuseppe; Arra, Claudio; Mallardo, Massimo; Buonaguro, Franco Maria; Scala, Giuseppe; Quinto, Ileana

    2015-01-01

    Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4(+) and CD8(+) T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation. PMID:26343909

  11. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study.

    PubMed

    Kaspar, Felix; Jelinek, Herbert F; Perkins, Steven; Al-Aubaidy, Hayder A; deJong, Bev; Butkowski, Eugene

    2016-01-01

    Objective. This study compared acute and late effect of single-bout endurance training (ET) and high-intensity interval training (HIIT) on the plasma levels of four inflammatory cytokines and C-reactive protein and insulin-like growth factor 1. Design. Cohort study with repeated-measures design. Methods. Seven healthy untrained volunteers completed a single bout of ET and HIIT on a cycle ergometer. ET and HIIT sessions were held in random order and at least 7 days apart. Blood was drawn before the interventions and 30 min and 2 days after the training sessions. Plasma samples were analyzed with ELISA for the interleukins (IL), IL-1β, IL-6, and IL-10, monocyte chemoattractant protein-1 (MCP-1), insulin growth factor 1 (IGF-1), and C-reactive protein (CRP). Statistical analysis was with Wilcoxon signed-rank tests. Results. ET led to both a significant acute and long-term inflammatory response with a significant decrease at 30 minutes after exercise in the IL-6/IL-10 ratio (-20%; p = 0.047) and a decrease of MCP-1 (-17.9%; p = 0.03). Conclusion. This study demonstrates that ET affects the inflammatory response more adversely at 30 minutes after exercise compared to HIIT. However, this is compensated by a significant decrease in MCP-1 at two days associated with a reduced risk of atherosclerosis. PMID:27212809

  12. Asian Sand Dust Enhances the Inflammatory Response and Mucin Gene Expression in the Middle Ear

    PubMed Central

    Chang, Jiwon; Go, Yoon Young; Park, Moo Kyun; Chae, Sung-Won; Lee, Seon-Heui; Song, Jae-Jun

    2016-01-01

    Objectives. Asia sand dust (ASD) is known to cause various human diseases including respiratory infection. The aim of this study was to examine the effect of ASD on inflammatory response in human middle ear epithelial cells (HMEECs) in vitro and in vivo. Methods. Cell viability was assessed using the cell counting kit-8 assay. The mRNA levels of various genes including COX-2, TNF-a, MUC 5AC, MUC 5B, TP53, BAX, BCL-2, NOX4, and SOD1 were analyzed using semiquantitative realtime polymerase chain reaction. COX-2 protein levels were determined by western blot analysis. Sprague Dawley rats were used for in vivo investigations of inflammatory reactions in the middle ear epithelium as a result of ASD injection. Results. We observed dose-dependent decrease in HMEEC viability. ASD exposure significantly increased COX-2, TNF-a, MUC5AC, and MUC5B mRNA expression. Also, ASD affected the mRNA levels of apoptosis- and oxidative stress-related genes. Western blot analysis revealed a dose-dependent increase in COX-2 production. Animal studies also demonstrated an ASD-induced inflammatory response in the middle ear epithelium. Conclusion. Environmental ASD exposure can result in the development of otitis media. PMID:27095518

  13. HMGB1 Promotes Systemic Lupus Erythematosus by Enhancing Macrophage Inflammatory Response

    PubMed Central

    Lu, Mudan; Yu, Shanshan; Gao, Bo; Xiong, Sidong

    2015-01-01

    Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE); however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure. Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues. Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-α and IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response. Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE. PMID:26078984

  14. Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Mandard, Stéphane; Patsouris, David

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARα and PPARβ/δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits. PMID:23577023

  15. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication.

    PubMed

    Wang, Gefei; Li, Rui; Jiang, Zhiwu; Gu, Liming; Chen, Yanxia; Dai, Jianping; Li, Kangsheng

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  16. Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection

    PubMed Central

    Howe, Charles L.; LaFrance-Corey, Reghann G.; Sundsbak, Rhianna S.; Sauer, Brian M.; LaFrance, Stephanie J.; Buenz, Eric J.; Schmalstieg, William F.

    2012-01-01

    Neuronal injury during acute viral infection of the brain is associated with the development of persistent cognitive deficits and seizures in humans. In C57BL/6 mice acutely infected with the Theiler's murine encephalomyelitis virus, hippocampal CA1 neurons are injured by a rapid innate immune response, resulting in profound memory deficits. In contrast, infected SJL and B6xSJL F1 hybrid mice exhibit essentially complete hippocampal and memory preservation. Analysis of brain-infiltrating leukocytes revealed that SJL mice mount a sharply attenuated inflammatory monocyte response as compared to B6 mice. Bone marrow transplantation experiments isolated the attenuation to the SJL immune system. Adoptive transfer of B6 inflammatory monocytes into acutely infected B6xSJL hosts converted these mice to a hippocampal damage phenotype and induced a cognitive deficit marked by failure to recognize a novel object. These findings show that inflammatory monocytes are the critical cellular mediator of hippocampal injury during acute picornavirus infection of the brain. PMID:22848791

  17. Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses.

    PubMed

    Chung, Jiwoo; Ku, Sae-Kwang; Lee, Suyeon; Bae, Jong-Sup

    2016-06-10

    Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. PMID:27155157

  18. Fluoxetine treatment prevents the inflammatory response in a mouse model of posttraumatic stress disorder.

    PubMed

    Kao, Chi-Ya; He, Zhisong; Zannas, Anthony S; Hahn, Oliver; Kühne, Claudia; Reichel, Judith M; Binder, Elisabeth B; Wotjak, Carsten T; Khaitovich, Philipp; Turck, Christoph W

    2016-05-01

    Despite intense research efforts the molecular mechanisms affecting stress-vulnerable brain regions in posttraumatic stress disorder (PTSD) remain elusive. In the current study we have applied global transcriptomic profiling to a PTSD mouse model induced by foot shock fear conditioning. We compared the transcriptomes of prelimbic cortex, anterior cingulate cortex (ACC), basolateral amygdala, central nucleus of amygdala, nucleus accumbens (NAc) and CA1 of the dorsal hippocampus between shocked and non-shocked (control) mice, with and without fluoxetine treatment by RNA sequencing. Differentially expressed (DE) genes were identified and clustered for in silico pathway analysis. Findings in relevant brain regions were further validated with immunohistochemistry. DE genes belonging to 11 clusters were identified including increased inflammatory response in ACC in shocked mice. In line with this finding, we noted higher microglial activation in ACC of shocked mice. Chronic fluoxetine treatment initiated in the aftermath of the trauma prevented inflammatory gene expression alterations in ACC and ameliorated PTSD-like symptoms, implying an important role of the immune response in PTSD pathobiology. Our results provide novel insights into molecular mechanisms affected in PTSD and suggest therapeutic applications with anti-inflammatory agents. PMID:26897419

  19. The elongation factor Spt5 facilitates transcription initiation for rapid induction of inflammatory-response genes

    PubMed Central

    Diamant, Gil; Bahat, Anat; Dikstein, Rivka

    2016-01-01

    A subset of inflammatory-response NF-κB target genes is activated immediately following pro-inflammatory signal. Here we followed the kinetics of primary transcript accumulation after NF-κB activation when the elongation factor Spt5 is knocked down. While elongation rate is unchanged, the transcript synthesis at the 5′-end and at the earliest time points is delayed and reduced, suggesting an unexpected role in early transcription. Investigating the underlying mechanism reveals that the induced TFIID–promoter association is practically abolished by Spt5 depletion. This effect is associated with a decrease in promoter-proximal H3K4me3 and H4K5Ac histone modifications that are differentially required for rapid transcriptional induction. In contrast, the displacement of TFIIE and Mediator, which occurs during promoter escape, is attenuated in the absence of Spt5. Our findings are consistent with a central role of Spt5 in maintenance of TFIID–promoter association and promoter escape to support rapid transcriptional induction and re-initiation of inflammatory-response genes. PMID:27180651

  20. A sumoylation-dependent pathway mediating transrepression of inflammatory response genes by PPARγ

    PubMed Central

    Pascual, Gabriel; Fong, Amy L.; Ogawa, Sumito; Gamliel, Amir; Li, Andrew C.; Perissi, Valentina; Rose, David W.; Willson, Timothy; Rosenfeld, Michael G.; Glass, Christopher K.

    2005-01-01

    The peroxisome proliferator-activated receptor γ (PPARγ) plays essential roles in adipogenesis and glucose homeostasis and is a molecular target of insulin-sensitizing drugs1–3. Although the ability of PPARγ agonists to antagonize inflammatory responses by transrepression of nuclear factor kappaB (NF-κB) target genes is linked to anti-diabetic4 and antiatherogenic actions5, the mechanisms remain poorly understood. Here we report the identification of a molecular pathway by which PPARγ represses transcriptional activation of inflammatory response genes in macrophages. The initial step of this pathway involves ligand-dependent sumoylation of the PPARγ ligand-binding domain, which targets PPARγ to nuclear receptor co-repressor (NCoR)/histone deacetylase-3 (HDAC3) complexes on inflammatory gene promoters. This in turn prevents recruitment of the ubiquitylation/19S proteosome machinery that normally mediates the signal-dependent removal of corepressor complexes required for gene activation. As a result, NCoR complexes are not cleared from the promoter and target genes are maintained in a repressed state. This mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-κB target genes that regulate immunity and homeostasis. PMID:16127449

  1. Possible involvement of soluble B7-H4 in T cell-mediated inflammatory immune responses.

    PubMed

    Kamimura, Yosuke; Kobori, Hiroko; Piao, Jinhua; Hashiguchi, Masaaki; Matsumoto, Koichiro; Hirose, Sachiko; Azuma, Miyuki

    2009-11-13

    B7-H4, a newly identified B7 family molecule, is reported to regulate T cell activation. However, the expression and function of B7-H4 remain controversial. Here, we demonstrated that B7-H4 expression in immune cells was undetectable at both the transcription and cell-surface protein levels. B7-H4 transfectants augmented anti-CD3 mAb-induced re-directed cytotoxicity and this was inhibited by anti-B7-H4 mAb. In a hapten-induced contact hypersensitivity model, treatment with anti-B7-H4 mAb at sensitization, but not at challenge, efficiently suppressed the ear swelling and CD8(+) T cell activation assessed by CD25 expression and IFN-gamma production. We found that cells expressing B7-H4 secreted soluble B7-H4 and the serum B7-H4 level increased with disease progression in lupus-prone and collagen-induced arthritis autoimmune mice and after the antigen challenge in allergic inflammatory diseases. Our results suggest a different action of B7-H4 in T cell-mediated inflammatory responses and the possible involvement of soluble B7-H4 in inflammatory immune responses. PMID:19723502

  2. The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis

    PubMed Central

    Barbarin, Virginie; Nihoul, Aurélie; Misson, Pierre; Arras, Mohammed; Delos, Monique; Leclercq, Isabelle; Lison, Dominique; Huaux, Francois

    2005-01-01

    Background It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged. Methods Using biochemical, histological, immunohistochemistry, and cellular analyses, we compared the lung responses (inflammation and fibrosis) to fibrogenic silica particles (2.5 and 25 mg/g lung) in Sprague-Dawley rats and NMRI mice. Results Rats treated with silica particles developed chronic and progressive inflammation accompanied by an overproduction of TNF-α as well as an intense lung fibrosis. Dexamethasone or pioglitazone limited the amplitude of the lung fibrotic reaction to silica in rats, supporting the paradigm that inflammation drives lung fibrosis. In striking contrast, in mice, silica induced only a limited and transient inflammation without TNF-α overproduction. However, mice developed lung fibrosis of a similar intensity than rats. The fibrotic response in mice was accompanied by a high expression of the anti-inflammatory and fibrotic cytokine IL-10 by silica-activated lung macrophages. In mice, IL-10 was induced only by fibrotic particles and significantly expressed in the lung of silica-sensitive but not silica-resistant strains of mice. Anti-inflammatory treatments did not control lung fibrosis in mice. Conclusion These results indicate that, beside chronic lung inflammation, a pronounced anti-inflammatory reaction may also contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis. PMID:16212659

  3. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

    PubMed Central

    Jiang, Zhiwu; Gu, Liming; Chen, Yanxia

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  4. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes.

    PubMed

    Itoi, Saori; Terao, Mika; Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs. PMID:24055708

  5. Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

    PubMed Central

    Connelly, Carey E.; Sun, Yezhou

    2012-01-01

    Throughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogen Bordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (ΔPT) B. pertussis. ΔPT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (ΔPThigh) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for ΔPThigh infection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to ΔPThigh-infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peak B. pertussis infection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms. PMID:23027529

  6. Flavonoid fraction of Bergamot juice reduces LPS-induced inflammatory response through SIRT1-mediated NF-κB inhibition in THP-1 monocytes.

    PubMed

    Risitano, Roberto; Currò, Monica; Cirmi, Santa; Ferlazzo, Nadia; Campiglia, Pietro; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

    2014-01-01

    Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-κB signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-κB inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) by a mechanism involving the inhibition of NF-κB activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-κB-mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process. PMID:25260046

  7. Equol suppresses inflammatory response and bone erosion due to rheumatoid arthritis in mice.

    PubMed

    Lin, I-Chian; Yamashita, Shuya; Murata, Motoki; Kumazoe, Motofumi; Tachibana, Hirofumi

    2016-06-01

    Rheumatoid arthritis (RA) is a chronic and systemic autoimmune inflammatory disease. Typical pathological findings of RA include persistent synovitis and bone degradation in the peripheral joints. Equol, a metabolite of the major soybean isoflavone daidzein, shows superior bioactivity than other isoflavones. We investigated the effects of equol administration on inflammatory response and bone erosion in mice with collagen-induced arthritis (CIA). The severity of arthritis symptoms was significantly low in the equol-administered CIA mice. In addition, equol administration improved the CIA-induced bone mineral density decline. In the inflamed area of CIA mice, equol administration suppressed the expression of interleukin-6 and its receptor. Furthermore, equol reduced the expression of genes associated with bone formation inhibition, osteoclast and immature osteoblast specificity and cartilage destruction. These results suggest that equol suppresses RA development and RA-induced bone erosion by regulating inflammation and bone metabolism. PMID:27142742

  8. Host Inflammatory Response to Mosquito Bites Enhances the Severity of Arbovirus Infection.

    PubMed

    Pingen, Marieke; Bryden, Steven R; Pondeville, Emilie; Schnettler, Esther; Kohl, Alain; Merits, Andres; Fazakerley, John K; Graham, Gerard J; McKimmie, Clive S

    2016-06-21

    Aedes aegypti mosquitoes are responsible for transmitting many medically important viruses such as those that cause Zika and dengue. The inoculation of viruses into mosquito bite sites is an important and common stage of all mosquito-borne virus infections. We show, using Semliki Forest virus and Bunyamwera virus, that these viruses use this inflammatory niche to aid their replication and dissemination in vivo. Mosquito bites were characterized by an edema that retained virus at the inoculation site and an inflammatory influx of neutrophils that coordinated a localized innate immune program that inadvertently facilitated virus infection by encouraging the entry and infection of virus-permissive myeloid cells. Neutrophil depletion and therapeutic blockade of inflammasome activity suppressed inflammation and abrogated the ability of the bite to promote infection. This study identifies facets of mosquito bite inflammation that are important determinants of the subsequent systemic course and clinical outcome of virus infection. PMID:27332734

  9. Possible Implication of Local Immune Response in Darier's Disease: An Immunohistochemical Characterization of Lesional Inflammatory Infiltrate

    PubMed Central

    Miracco, Clelia; Pietronudo, Francesco; Mourmouras, Vasileios; Pellegrino, Michele; Onorati, Monica; Mastrogiulio, Maria Grazia; Cantarini, Luca; Luzi, Pietro

    2010-01-01

    Cell-mediated immunity is considered to be normal in Darier's Disease (DD), an inherited skin disorder complicated by skin infections. To date, there are no investigations on the local inflammatory infiltrate in DD skin lesions. In this immunohistochemical study we characterized and quantified it, making comparisons with two other inflammatory skin disorders, that is, pemphigus vulgaris (PV) and lichen ruber planus (LRP), and with the normal skin (NSk). We found a significant (P < .05) decrease of CD1a+ Langerhans cells (LCs) in DD, compared to PV, LRP, and NSk, and of CD123+ plasmacytoid dendritic cells (pDCs), compared to PV and LRP. We hypothesize that the genetic damage of keratinocytes might result in a loss of some subsets of dendritic cells and, consequently, in an impaired local immune response, which might worsen the infections that inevitably occur in this disease. PMID:20671948

  10. TLR4-dependent activation of inflammatory cytokine response in macrophages by Francisella elongation factor Tu1

    PubMed Central

    Sharma, Jyotika; Mishra, Bibhuti B.; Li, Qun; Teale, Judy M.

    2011-01-01

    The bacterial determinants of pulmonary Francisella induced inflammatory responses and their interaction with host components are not clearly defined. In this study, proteomic and immunoblot analyses showed presence of a cytoplasmic protein elongation factor Tu (EF-Tu) in the membrane fractions of virulent F. novicida, LVS and SchuS4, but not in an attenuated F. novicida mutant. EF-Tu was immunodominant in mice vaccinated and protected from virulent F. novicida. Moreover, recombinant EF-Tu induced macrophages to produce inflammatory cytokines in a TLR4 dependent manner. This study shows immune stimulatory properties of a cytoplasmic protein EF-Tu expressed on the membrane of virulent Francisella strains. PMID:21497800

  11. Inflammatory mammary carcinoma in 12 dogs: Clinical features, cyclooxygenase-2 expression, and response to piroxicam treatment

    PubMed Central

    de M. Souza, Carlos H.; Toledo-Piza, Evandro; Amorin, Renee; Barboza, Andrigo; Tobias, Karen M.

    2009-01-01

    Canine inflammatory mammary carcinoma (IMC) is a rare, locally aggressive, highly metastatic tumor that is poorly responsive to treatment. The purposes of this study were to retrospectively evaluate the history, signalment, and clinical signs of dogs with IMC; compare the outcome of affected dogs treated with traditional chemotherapy with those treated with piroxicam; evaluate Cox-2 expression of IMC cells; and correlate Cox-2 expression with outcome based on treatment. Strong cyclooxygenase-2 expression was present in all tumors. Improvement in clinical condition and disease stability was achieved in all dogs treated with piroxicam, with mean and median progression-free survival of 171 and 183 days, respectively. Median survival time of 3 dogs treated with doxorubicin-based protocols was 7 days, which was significantly less than that of dogs treated with piroxicam (median, 185 days). In conclusion, piroxicam should be considered as a single agent for the treatment of dogs with inflammatory mammary carcinoma. PMID:19436636

  12. Atypical Chemokine Receptors and Their Roles in the Resolution of the Inflammatory Response

    PubMed Central

    Bonecchi, Raffaella; Graham, Gerard J.

    2016-01-01

    Chemokines and their receptors are key mediators of the inflammatory process regulating leukocyte extravasation and directional migration into inflamed and infected tissues. The control of chemokine availability within inflamed tissues is necessary to attain a resolving environment and when this fails chronic inflammation ensues. Accordingly, vertebrates have adopted a number of mechanisms for removing chemokines from inflamed sites to help precipitate resolution. Over the past 15 years, it has become apparent that essential players in this process are the members of the atypical chemokine receptor (ACKR) family. Broadly speaking, this family is expressed on stromal cell types and scavenges chemokines to either limit their spatial availability or to remove them from in vivo sites. Here, we provide a brief review of these ACKRs and discuss their involvement in the resolution of inflammatory responses and the therapeutic implications of our current knowledge. PMID:27375622

  13. Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses

    PubMed Central

    Aho, Vilma; Ollila, Hanna M.; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J.; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S.A.; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M.; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T.; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

    2016-01-01

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases. PMID:27102866

  14. Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

    PubMed

    Aho, Vilma; Ollila, Hanna M; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S A; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

    2016-01-01

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases. PMID:27102866

  15. [Association of fatty acid metabolism with systemic inflammatory response in chronic respiratory diseases].

    PubMed

    Denisenko, Y K; Novgorodtseva, T P; Zhukova, N V; Antonuk, M V; Lobanova, E G; Kalinina, E P

    2016-03-01

    We examined composition of plasma non-esterified fatty acids (NFAs), erythrocyte fatty acids, levels of eicosanoids in patients with asthma and chronic obstructive pulmonary disease (COPD) with different type of the inflammatory response. The results of our study show that asthma and COPD in remission are associated with changes in the composition NFAs of plasma, FA of erythrocytes, level eicosanoid despite the difference in the regulation of immunological mechanisms of systemic inflammation. These changes are characterized by excessive production of arachidonic acid (20:4n-6) and cyclooxygenase and lipoxygenase metabolites (thromboxane B2, leukotriene B4) and deficiency of their functional antagonist, eicosapentaenoic acid (20:5n-3). The recognized association between altered fatty acid composition and disorders of the immune mechanisms of regulation of systemic inflammation in COPD and asthma demonstrated the important role of fatty acids and their metabolites in persistence of inflammatory processes in diseases of the respiratory system in the condition of remission. PMID:27420629

  16. Biocompatibility, Inflammatory Response, and Recannalization Characteristics of Nonradioactive Resin Microspheres: Histological Findings

    SciTech Connect

    Bilbao, Jose I.; Martino, Alba de; Luis, Esther de; Diaz-Dorronsoro, Lourdes; Alonso-Burgos, Alberto; Martinez de la Cuesta, Antonio; Sangro, Bruno; Garcia de Jalon, Jose A.

    2009-07-15

    Intra-arterial radiotherapy with yttrium-90 microspheres (radioembolization) is a therapeutic procedure exclusively applied to the liver that allows the direct delivery of high-dose radiation to liver tumors, by means of endovascular catheters, selectively placed within the tumor vasculature. The aim of the study was to describe the distribution of spheres within the precapillaries, inflammatory response, and recannalization characteristics after embolization with nonradioactive resin microspheres in the kidney and liver. We performed a partial embolization of the liver and kidney vessels in nine white pigs. The left renal and left hepatic arteries were catheterized and filled with nonradioactive resin microspheres. Embolization was defined as the initiation of near-stasis of blood flow, rather than total occlusion of the vessels. The hepatic circulation was not isolated so that the effects of reflux of microspheres into stomach could be observed. Animals were sacrificed at 48 h, 4 weeks, and 8 weeks, and tissue samples from the kidney, liver, lung, and stomach evaluated. Microscopic evaluation revealed clusters of 10-30 microspheres (15-30 {mu}m in diameter) in the small vessels of the kidney (the arciform arteries, vasa recti, and glomerular afferent vessels) and liver. Aggregates were associated with focal ischemia and mild vascular wall damage. Occlusion of the small vessels was associated with a mild perivascular inflammatory reaction. After filling of the left hepatic artery with microspheres, there was some evidence of arteriovenous shunting into the lungs, and one case of cholecystitis and one case of marked gastritis and ulceration at the site of arterial occlusion due to the presence of clusters of microspheres. Beyond 48 h, microspheres were progressively integrated into the vascular wall by phagocytosis and the lumen recannalized. Eight-week evaluation found that the perivascular inflammatory reaction was mild. Liver cell damage, bile duct injury, and

  17. Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2

    SciTech Connect

    Li, Bin; Abdalrahman, Akram; Lai, Yimu; Janicki, Joseph S.; Ward, Keith W.; Meyer, Colin J.; Wang, Xing Li; Tang, Dongqi; Cui, Taixing

    2014-02-21

    Highlights: • Dh404 suppresses the expression of a selected set of pro-inflammatory cytokines in inflamed macrophages via activating Nrf2. • Dh404 activates Nrf2 while keeping Keap1 function intact in macrophages. • Dh404 minimally regulates NF-κB pathway in macrophages. - Abstract: Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β), while minimally regulating the expression of interleulin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNFα). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-κB activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti-inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation

  18. Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor.

    PubMed

    Qin, Suofu; Ni, Ming; Wang, Xiuyun; Maurier-Mahé, Florence; Shurland, Dixie-Lee; Rodrigues, Gerard A

    2011-12-01

    Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis. Cellular extracts can trigger ARPE-19 cell inflammatory responses, producing cytokines that lead to an increase in ARPE-19 cell monolayer permeability. Addition of recombinant HSP90β mimics the induction of chemokines IL-8 and MCP-1 in cultured RPE cells, suggesting that released HSP90 can incite RPE cell sterile inflammatory responses. Consistent with this, classical HSP90 inhibitors were shown to substantially reduce necrosis-induced cytokine production and permeability increases in ARPE-19 cells. Moreover, a cell-impermeable inhibitor, 17-N,N-dimethylaminoethylamino-17-demethoxy-geldanamycin-N-oxide, also efficiently inhibited necrosis-induced cytokine production and TNF-α/IL-1β-induced increase in ARPE-19 cell permeability in vitro and endotoxin-induced development of uveitis in vivo, suggesting that HSP90 can contribute to necrosis-induced RPE inflammatory responses. Collectively, our data identify HSP90 as a pro-inflammatory molecule in RPE cell sterile inflammatory responses. PMID:22019372

  19. Dexmedetomidine decreases the inflammatory response to myocardial surgery under mini-cardiopulmonary bypass

    PubMed Central

    Bulow, N.M.H.; Colpo, E.; Pereira, R.P.; Correa, E.F.M.; Waczuk, E.P.; Duarte, M.F.; Rocha, J.B.T.

    2016-01-01

    Cardiopulmonary bypass (CPB) with extracorporeal circulation produces changes in the immune system accompanied by an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines. We hypothesize that dexmedetomidine (DEX) as an anesthetic adjuvant modulates the inflammatory response after coronary artery bypass graft surgery with mini-CPB. In a prospective, randomized, blind study, 12 patients (4 females and 8 males, age range 42-72) were assigned to DEX group and compared with a conventional total intravenous anesthesia (TIVA) group of 11 patients (4 females and 7 males). The endpoints used to assess inflammatory and biochemical responses to mini-CPB were plasma interleukin (IL)-1, IL-6, IL-10, interferon (INF)-γ, tumor necrosis factor (TNF)-α, C-reactive protein, creatine phosphokinase, creatine phosphokinase-MB, cardiac troponin I, cortisol, and glucose levels. These variables were determined before anesthesia, 90 min after beginning CPB, 5 h after beginning CPB, and 24 h after the end of surgery. Endpoints of oxidative stress, including thiobarbituric acid reactive species and delta-aminolevulinate dehydratase activity in erythrocytes were also determined. DEX+TIVA use was associated with a significant reduction in IL-1, IL-6, TNF-α, and INF-γ (P<0.0001) levels compared with TIVA (two-way ANOVA). In contrast, the surgery-induced increase in thiobarbituric acid reactive species was higher in the DEX+TIVA group than in the TIVA group (P<0.01; two-way ANOVA). Delta-aminolevulinate dehydratase activity was decreased after CPB (P<0.001), but there was no difference between the two groups. DEX as an adjuvant in anesthesia reduced circulating IL-1, IL-6, TNF-α, and INF-γ levels after mini-CPB. These findings indicate an interesting anti-inflammatory effect of DEX, which should be studied in different types of surgical interventions. PMID:26909786

  20. Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise.

    PubMed

    Hamada, Koichiro; Vannier, Edouard; Sacheck, Jennifer M; Witsell, Alice L; Roubenoff, Ronenn

    2005-02-01

    The impact of aging on the cytokine response of human skeletal muscle to exercise-induced injury remains poorly understood. We enrolled physically active, young (23-35 years old, n=15) and old (66-78 years old, n=15) men to perform 45 min of downhill running (16% descent) at 75% VO2max. Biopsies of vastus lateralis were obtained 24 h before and 72 h after acute eccentric exercise. Transcripts for inflammatory (TNF-alpha, IL-1beta) and anti-inflammatory cytokines (IL-6, TGF-beta1) were quantified by real-time PCR. Before exercise, cytokine transcripts did not differ with age. At old age, exercise induced a blunted accumulation of transcripts encoding the pan-leukocyte surface marker CD18 (young: 10.1-fold increase, P<0.005; old: 4.7-fold increase, P=0.02; young vs. old: P<0.05). In both age groups, CD18 transcript accumulation strongly correlated with TNF-alpha (young, r=0.87, P<0.001; old, r=0.72, P=0.002) and TGF-beta1 transcript accumulation (young, r=0.80, P<0.001; old, r=0.64, P=0.008). At old age, there was no correlation between IL-1beta and CD18 transcript accumulation. Furthermore, exercise induced IL-6 transcript accumulation in young (3.6-fold, P=0.057) but not in old men. Our results suggest that aging impairs the adaptive response of human skeletal muscle to eccentric exercise by differential modulation of a discrete set of inflammatory and anti-inflammatory cytokine genes. PMID:15556970

  1. Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure

    NASA Technical Reports Server (NTRS)

    Johnston, C. J.; Finkelstein, J. N.; Gelein, R.; Baggs, R.; Oberdorster, G.; Clarkson, T. W. (Principal Investigator)

    1996-01-01

    Heating of polytetrafluoroethylene (PTFE) has been described to release fumes containing ultrafine particles (approximately 18 nm diam). These fumes can be highly toxic in the respiratory tract inducing extensive pulmonary edema with hemorrhagic inflammation. Fischer-344 rats were exposed to PTFE fumes generated by temperatures ranging from 450 to 460 degrees C for 15 min at an exposure concentration of 5 x 10(5) particles/cm3, equivalent to approximately 50 micrograms/m3. Responses were examined 4 hr post-treatment when these rats demonstrated 60-85% neutrophils (PMNs) in their lung lavage. Increases in abundance for messages encoding the antioxidants manganese superoxide dismutase and metallothionein (MT) increased 15- and 40-fold, respectively. For messages encoding the pro- and anti-inflammatory cytokines: inducible nitric oxide synthase, interleukin 1 alpha, 1 beta, and 6 (IL-1 alpha, IL-1 beta, and IL-6), macrophage inflammatory protein-2, and tumor necrosis factor-alpha (TNF alpha) increases of 5-, 5-, 10-, 40-, 40-, and 15-fold were present. Vascular endothelial growth factor, which may play a role in the integrity of the endothelial barrier, was decreased to 20% of controls. In situ sections were hybridized with 33P cRNA probes encoding IL-6, MT, surfactant protein C, and TNF alpha. Increased mRNA abundance for MT and IL-6 was expressed around all airways and interstitial regions with MT and IL-6 demonstrating similar spatial distribution. Large numbers of activated PMNs expressed IL-6, MT, and TNF alpha. Additionally, pulmonary macrophages and epithelial cells were actively involved. These observations support the notion that PTFE fumes containing ultrafine particles initiate a severe inflammatory response at low inhaled particle mass concentrations, which is suggestive of an oxidative injury. Furthermore, PMNs may actively regulate the inflammatory process through cytokine and antioxidant expression.

  2. Pulmonary and systemic inflammatory responses to intra-amniotic IL-1α in fetal sheep

    PubMed Central

    Kramer, Boris W.; Nitsos, Ilias; Pillow, J. Jane; Collins, Jennifer J. P.; Polglase, Graeme R.; Newnham, John P.; Jobe, Alan H.

    2011-01-01

    Clinical and epidemiological studies implicate IL-1 as an important mediator of perinatal inflammation. We tested the hypothesis that intra-amniotic IL-1α would induce pulmonary and systemic fetal inflammatory responses. Sheep with singleton fetuses were given an intra-amniotic injection of recombinant sheep IL-1α (100 μg) and were delivered 1, 3, or 7 days later, at 124 ± 1 days gestation (n=5–8/group). A separate group of sheep were given two intra-amniotic IL-1α injections (100 μg dose each): 7 days and again 1 day prior to delivery. IL-1α induced a robust increase in monocytes, neutrophils, lymphocytes, and IL-8 protein in bronchoalveolar lavage fluid. H2O2 secretion was increased in inflammatory cells isolated from lungs of IL-1α-exposed lambs upon LPS challenge in vitro compared with control monocytes. T lymphocytes were recruited to the lung. IL-1β, cyclooxygenase-1, and cyclooxygenase-2 mRNA expression increased in the lung 1 day after intra-amniotic IL-1α exposure. Lung volumes increased 7 days after intra-amniotic IL-1α exposure, with minimal anatomic changes in air space morphology. The weight of the posterior mediastinal lymph node draining the lung and the gastrointestinal tract doubled, inducible nitric oxide synthase (NOSII)-positive cells increased, and Foxp3-positive T-regulatory lymphocytes decreased in the lymph node after IL-1α exposure. In the blood, neutrophil counts and plasma haptoglobin increased after IL-1α exposure. Compared with a single exposure, exposure to intra-amniotic IL-1α 7 days and again 1 day before delivery had a variable effect (increases in some inflammatory markers, but not pulmonary cytokines). IL-1α is a potent mediator of the fetal inflammatory response syndrome. PMID:21665964

  3. Cervical sympathetic block regulates early systemic inflammatory response in severe trauma patients

    PubMed Central

    Liu, Ming-Hua; Tian, Jun; Su, Yong-Ping; Wang, Tao; Xiang, Qiang; Wen, Liang

    2013-01-01

    Background This aim of this study was to investigate the effects of one-side cervical sympathetic block on early inflammatory response in severe trauma patients. Material/Methods Thirty severe trauma patients with injury severity score (ISS) of 16 to 25 were randomly divided into treatment and control groups (n=15 each). Patients in the treatment group underwent a right-side stellate ganglion block (SGB) using 8 mL 0.75% ropivacaine for 4 times, with the first injection within 12 hr of admission and the other 3 injections were 12 hr, 24 hr and 48 hr later. The same procedures were performed for the control group except that normal saline was injected instead of ropivacaine. Blood was collected before injection and at 6 hr, 24 hr, and 72 hr after the first SGB for serum interleukin (IL)-1β, IL-4, IL-6, IL-10 and TNF-α measurement. Results The concentrations of IL-1β, IL-6, and TNF-α between 24 hr to 72 hr after SGB were all significantly lower than those in the control group (all P values <0.01). However, there was no significant difference in the concentrations of anti-inflammatory IL-4 and IL-10 between treatment and control groups. There was no obvious impact of SGB on breathing and circulation except for a slower heart rate 10 to 50 min after injection (P<0.01). Conclusions SGB regulates early inflammatory response through inhibition of the proinflammatory cytokines IL-1β, IL-6, and TNF-α during severe trauma. SGB has no impact on the levels of anti-inflammatory cytokines IL-4 and IL-10. PMID:23492458

  4. Effect of triacontanol on numbers and functions of cells involved in inflammatory responses.

    PubMed

    Warren, R P; Burger, R A; Sidwell, R W; Clark, L L

    1992-07-01

    A preparation of a triacontanol-containing compound was studied for its effect on cells involved in the inflammatory response. C57BL/6 mice were injected intraperitoneally with various concentrations of this compound and investigated for total body weight, wet weight of thymus tissue, number of thymus cells and splenocytes, interleukin 1 production of spleen monocytes, and response of splenocytes to the T cell mitogen, phytohemagglutinin. Mice treated with the triacontanol preparation exhibited decreased total body weight, 24% reduction in thymus weights, 39% decrease in the number of thymus cells, and 21% depression in total splenocytes. Splenic monocytes of these animals produced a significantly reduced amount of interleukin 1 and splenocytes had a significantly depressed response to phytohemagglutinin. It is concluded that triacontanol has an inhibitory effect on at least some of the cells responsible for inflammation. PMID:1615010

  5. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    SciTech Connect

    Itoi, Saori; Terao, Mika Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol

  6. Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase

    PubMed Central

    Tchivileva, Inna E; Nackley, Andrea G; Qian, Li; Wentworth, Sean; Conrad, Matthew; Diatchenko, Luda B

    2009-01-01

    Background Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Specifically, low COMT activity is associated with heightened pain perception and development of musculoskeletal pain in humans as well as increased experimental pain sensitivity in rodents. Results We report that the proinflammatory cytokine tumor necrosis factor α (TNFα) downregulates COMT mRNA and protein in astrocytes. Examination of the distal COMT promoter (P2-COMT) reveals a putative binding site for nuclear factor κB (NF-κB), the pivotal regulator of inflammation and the target of TNFα. Cell culture assays and functional deletion analyses of the cloned P2-COMT promoter demonstrate that TNFα inhibits P2-COMT activity in astrocytes by inducing NF-κB complex recruitment to the specific κB binding site. Conclusion Collectively, our findings provide the first evidence for NF-κB-mediated inhibition of COMT expression in the central nervous system, suggesting that COMT contributes to the pathogenesis of inflammatory pain states. PMID:19291302

  7. Tumor suppressor death-associated protein kinase attenuates inflammatory responses in the lung.

    PubMed

    Nakav, Sigal; Cohen, Shmuel; Feigelson, Sara W; Bialik, Shani; Shoseyov, David; Kimchi, Adi; Alon, Ronen

    2012-03-01

    Death-associated protein kinase (DAPk) is a tumor suppressor thought to inhibit cancer by promoting apoptosis and autophagy. Because cancer progression is linked to inflammation, we investigated the in vivo functions of DAPk in lung responses to various acute and chronic inflammatory stimuli. Lungs of DAPk knockout (KO) mice secreted higher concentrations of IL-6 and keratinocyte chemoattractant (or chemokine [C-X-C motif] ligand 1) in response to transient intranasal administrations of the Toll-like receptor-4 (TLR4) agonist LPS. In addition, DAPk-null macrophages and neutrophils were hyperresponsive to ex vivo stimulation with LPS. DAPk-null neutrophils were also hyperresponsive to activation via Fc receptor and Toll-like receptor-3, indicating that the suppressive functions of this kinase are not restricted to TLR4 pathways. Even after the reconstitution of DAPk-null lungs with DAPk-expressing leukocytes by transplanting wild-type (WT) bone marrow into lethally irradiated DAPk KO mice, the chimeric mice remained hypersensitive to both acute and chronic LPS challenges, as well as to tobacco smoke exposure. DAPk-null lungs reconstituted with WT leukocytes exhibited elevated neutrophil content and augmented cytokine secretion in the bronchoalveolar space, as well as enhanced epithelial cell injury in response to both acute and chronic inflammatory conditions. These results suggest that DAPk attenuates a variety of inflammatory responses, both in lung leukocytes and in lung epithelial cells. The DAPk-mediated suppression of lung inflammation and airway injury may contribute to the tumor-suppressor functions of this kinase in epithelial carcinogenesis. PMID:21997486

  8. Uncoupling between Inflammatory and Fibrotic Responses to Silica: Evidence from MyD88 Knockout Mice

    PubMed Central

    Lo Re, Sandra; Yakoub, Yousof; Devosse, Raynal; Uwambayinema, Francine; Couillin, Isabelle; Ryffel, Bernard; Marbaix, Etienne; Lison, Dominique; Huaux, François

    2014-01-01

    The exact implication of innate immunity in granuloma formation and irreversible lung fibrosis remains to be determined. In this study, we examined the lung inflammatory and fibrotic responses to silica in MyD88-knockout (KO) mice. In comparison to wild-type (WT) mice, we found that MyD88-KO animals developed attenuated lung inflammation, neutrophil accumulation and IL-1β release in response to silica. Granuloma formation was also less pronounced in MyD88-KO mice after silica. This limited inflammatory response was not accompanied by a concomitant attenuation of lung collagen accumulation after silica. Histological analyses revealed that while pulmonary fibrosis was localized in granulomas in WT animals, it was diffusely distributed throughout the parenchyma in MyD88-KO mice. Robust collagen accumulation was also observed in mice KO for several other components of innate immunity (IL-1R, IL-1, ASC, NALP3, IL-18R, IL-33R, TRIF, and TLR2-3-4,). We additionally show that pulmonary fibrosis in MyD88-KO mice was associated with the accumulation of pro-fibrotic regulatory T lymphocytes (T regs) and pro-fibrotic cytokine expression (TGF-β, IL-10 and PDGF-B), not with T helper (Th) 17 cell influx. Our findings indicate that the activation of MyD88-related innate immunity is central in the establishment of particle-induced lung inflammatory and granuloma responses. The development of lung fibrosis appears uncoupled from inflammation and may be orchestrated by a T reg-associated pathway. PMID:25050810

  9. Neural mechanisms linking social status and inflammatory responses to social stress.

    PubMed

    Muscatell, Keely A; Dedovic, Katarina; Slavich, George M; Jarcho, Michael R; Breen, Elizabeth C; Bower, Julienne E; Irwin, Michael R; Eisenberger, Naomi I

    2016-06-01

    Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions. PMID:26979965

  10. Mechanical Strain Causes Adaptive Change in Bronchial Fibroblasts Enhancing Profibrotic and Inflammatory Responses

    PubMed Central

    Manuyakorn, Wiparat; Smart, David E.; Noto, Antonio; Bucchieri, Fabio; Haitchi, Hans Michael; Holgate, Stephen T.; Howarth, Peter H.; Davies, Donna E.

    2016-01-01

    Asthma is characterized by periodic episodes of bronchoconstriction and reversible airway obstruction; these symptoms are attributable to a number of factors including increased mass and reactivity of bronchial smooth muscle and extracellular matrix (ECM) in asthmatic airways. Literature has suggested changes in cell responses and signaling can be elicited via modulation of mechanical stress acting upon them, potentially affecting the microenvironment of the cell. In this study, we hypothesized that mechanical strain directly affects the (myo)fibroblast phenotype in asthma. Therefore, we characterized responses of bronchial fibroblasts, from 6 normal and 11 asthmatic non-smoking volunteers, exposed to cyclical mechanical strain using flexible silastic membranes. Samples were analyzed for proteoglycans, α-smooth muscle actin (αSMA), collagens I and III, matrix metalloproteinase (MMP) 2 & 9 and interleukin-8 (IL-8) by qRT-PCR, Western blot, zymography and ELISA. Mechanical strain caused a decrease in αSMA mRNA but no change in either αSMA protein or proteoglycan expression. In contrast the inflammatory mediator IL-8, MMPs and interstitial collagens were increased at both the transcriptional and protein level. The results demonstrate an adaptive response of bronchial fibroblasts to mechanical strain, irrespective of donor. The adaptation involves cytoskeletal rearrangement, matrix remodelling and inflammatory cytokine release. These results suggest that mechanical strain could contribute to disease progression in asthma by promoting inflammation and remodelling responses. PMID:27101406

  11. N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response

    PubMed Central

    He, Ping; Srikrishna, Geetha; Freeze, Hudson H

    2014-01-01

    Congenital disorders of glycosylation (CDGs) result from mutations in various N-glycosylation genes. The most common type, phosphomannomutase-2 (PMM2)-CDG (CDG-Ia), is due to deficient PMM2 (Man-6-P → Man-1-P). Many patients die from recurrent infections, but the mechanism is unknown. We found that glycosylation-deficient patient fibroblasts have less intercellular adhesion molecule-1 (ICAM-1), and because of its role in innate immune response, we hypothesized that its reduction might help explain recurrent infections in CDG patients. We, therefore, studied mice with mutations in Mpi encoding phosphomannose isomerase (Fru-6-P → Man-6-P), the cause of human MPI-CDG. We challenged MPI-deficient mice with an intraperitoneal injection of zymosan to induce an inflammatory response and found decreased neutrophil extravasation compared with control mice. Immunohistochemistry of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM-1 response to acute peritonitis. Since phosphomannose isomerase (MPI)-CDG patients and their cells improve glycosylation when given mannose, we provided MPI-deficient mice with mannose-supplemented water for 7 days. This restored ICAM-1 expression on mesenteric endothelial cells and enhanced transendothelial migration of neutrophils during acute inflammation. Attenuated inflammatory response in glycosylation-deficient mice may result from a failure to increase ICAM-1 on the vascular endothelial surface and may help explain recurrent infections in patients. PMID:24474243

  12. Macrophage Internalization of Fungal β-Glucans Is Not Necessary for Initiation of Related Inflammatory Responses

    PubMed Central

    McCann, Frances; Carmona, Eva; Puri, Vishwajeet; Pagano, Richard E.; Limper, Andrew H.

    2005-01-01

    Cell wall β-glucans are highly conserved structural components of fungi that potently trigger inflammatory responses in an infected host. Identification of molecular mechanisms responsible for internalization and signaling of fungal β-glucans should enhance our understanding of innate immune responses to fungi. In this study, we demonstrated that internalization of fungal β-glucan particles requires actin polymerization but not participation of components of caveolar uptake mechanisms. Using fluorescence microscopy, we observed that uptake of 5-([4,6-dichlorotriazin-2-yl] amino)-fluorescein hydrochloride-Celite complex-labeled Saccharomyces cerevisiae β-glucan by RAW macrophages was substantially reduced in the presence of cytochalasin D, which antagonizes actin-mediated internalization pathways, but not by treatment with nystatin, which blocks caveolar uptake. Interestingly, β-glucan-induced NF-κB translocation, which is necessary for inflammatory activation, and tumor necrosis factor alpha production were both normal in the presence of cytochalasin D, despite defective internalization of β-glucan particles following actin disruption. Dectin-1, a major β-glucan receptor on macrophages, colocalized to phagocytic cups on macrophages and exhibited tyrosine phosphorylation after challenge with β-glucan particles. Dectin-1 localization and other membrane markers were not affected by treatment with cytochalasin D. Furthermore, dectin-1 receptors rather than Toll-like receptor 2 receptors were shown to be necessary for both efficient internalization of β-glucan particles and cytokine release in response to the fungal cell wall component. PMID:16177305

  13. Activation of inflammatory responses in human U937 macrophages by particulate matter collected from dairy farms: an in vitro expression analysis of pro-inflammatory markers

    PubMed Central

    2012-01-01

    Background The purpose of the present study was to investigate activation of inflammatory markers in human macrophages derived from the U937 cell line after exposure to particulate matter (PM) collected on dairy farms in California and to identify the most potent components of the PM. Methods PM from different dairies were collected and tested to induce an inflammatory response determined by the expression of various pro-inflammatory genes, such as Interleukin (IL)-8, in U937 derived macrophages. Gel shift and luciferase reporter assays were performed to examine the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like-receptor 4 (TLR4). Results Macrophage exposure to PM derived from dairy farms significantly activated expression of pro-inflammatory genes, including IL-8, cyclooxygenase 2 and Tumor necrosis factor-alpha, which are hallmarks of inflammation. Acute phase proteins, such as serum amyloid A and IL-6, were also significantly upregulated in macrophages treated with PM from dairies. Coarse PM fractions demonstrated more pro-inflammatory activity on an equal-dose basis than fine PM. Urban PM collected from the same region as the dairy farms was associated with a lower concentration of endotoxin and produced significantly less IL-8 expression compared to PM collected on the dairy farms. Conclusion The present study provides evidence that the endotoxin components of the particles collected on dairies play a major role in mediating an inflammatory response through activation of TLR4 and NF-κB signaling. PMID:22452745

  14. Crucial role of Toll-like receptors in the zinc/nickel-induced inflammatory response in vascular endothelial cells

    SciTech Connect

    Tsou, Tsui-Chun; Liou, Saou-Hsing; Yeh, Szu-Ching; Tsai, Feng-Yuan; Chao, How-Ran

    2013-12-15

    Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs in the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause

  15. Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environment-dependent.

    PubMed

    Liang, Dongchun; Zuo, Aijun; Shao, Hui; Chen, Mingjiazi; Kaplan, Henry J; Sun, Deming

    2014-12-01

    Adenosine is a key endogenous signaling molecule that regulates a wide range of physiological functions, including immune system function and inflammation. Studies have shown that adenosine receptor (AR) agonists can be either anti-inflammatory or proinflammatory in immune responses and in inflammation, and the clarification of the mechanisms causing these opposing effects should provide a better guide for therapeutic intervention. Whereas previous studies mostly examined the effects of AR agonists on Th1-type immune responses, in this study, we compared their effect on Th17 and Th1 autoimmune responses in experimental autoimmune uveitis, a mouse model of human uveitis induced by immunization with the human interphotoreceptor retinoid-binding protein peptides 1-20. We showed that injection of mice with a nonselective AR agonist, 5'-N-ethylcarboxamidoadenosine (NECA), at an early stage after immunization had an inhibitory effect on both Th1 and Th17 responses, whereas injection of the same amount of NECA at a late stage inhibited the Th1 response but had an enhancing effect on the Th17 response. We also showed that the effects of NECA on Th1 and Th17 responses were completely dissociated, that the enhancing effect of NECA on Th17 responses was modulated by γδ T cells, and that the response of γδ T cells to NECA was determined by their activation status. We conclude that the inflammatory environment has a strong impact on converting the effect of AR agonist on the Th17 autoimmune response from anti-inflammatory to proinflammatory. Our observation should help in the designing of better AR-targeted therapies. PMID:25367119

  16. Chronic low level arsenic exposure evokes inflammatory responses and DNA damage.

    PubMed

    Dutta, Kaustav; Prasad, Priyanka; Sinha, Dona

    2015-08-01

    The cross-sectional study investigated the impact of chronic low level arsenic (As) exposure (11-50μg/L) on CD14 expression and other inflammatory responses in rural women of West Bengal enrolled from control (As level <10μg/L; N, 131) and exposed area (As level 11-50μg/L, N, 142). Atomic absorption spectroscopy revealed that As level in groundwater was higher in endemic areas (22.93±10. 1 vs. 1.61±0.15, P<0.0001) and showed a positive correlation [Pearsons r, 0.9281; 95% confidence interval, 0.8192-0.9724] with As content in nails of the exposed women. Flow cytometric analysis showed that CD 14 expression on monocytes was significantly higher (P<0.001) in exposed women and positively correlated with groundwater As [Pearsons r, 0.9191; 95% confidence interval, 0.7584-0.9745]. Leucocytes and airway cells of As exposed women exhibited up regulation of an inflammatory mediator, tumor necrosis factor-α (TNF-α) and transcription factor, nuclear factor-κB (NF-κB) (P<0.0001). Plasma pro inflammatory cytokines like - TNF-α, interleukins (ILs) - IL-6, IL-8, IL-12 were elevated whereas anti-inflammatory cytokine IL-10 was depleted in the exposed women. Sputa of the exposed women had elevated activity of inflammatory markers - MMP-2 and MMP-9 whereas sera were observed with only increased activity of MMP-9. Airway cells of the exposed women had exacerbated DNA damage than control. Level of oxidative DNA adducts like 8-hydroxy-2'-deoxyguanosine (8OHdG) were also enhanced in plasma of exposed women. Therefore it might be indicated that low level As exposure elicited a pro-inflammatory profile which might have been contributed in part by CD14 expressing monocytes and prolong persistence of pulmonary and systemic inflammation might have promoted oxidative DNA damage in the rural women. PMID:26118750

  17. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.

    PubMed

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation. PMID:26617279

  18. Mutation of cysteine 46 in IKK-beta increases inflammatory responses

    PubMed Central

    Jiang, Zhi Hong; Jiang, Shui Ping; Liu, Yan; Wang, Ting Yu; Yao, Xiao Jun; Su, Xiao Hui; Yan, Feng Gen; Liu, Juan; Leung, Elaine Lai-Han; Yi, Xiao Qin; Wong, Yuen Fan; Zhou, Hua; Liu, Liang

    2015-01-01

    Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β−NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-βC46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-βC46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-β. PMID:26378659

  19. Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders.

    PubMed

    ten Oever, Jaap; Netea, Mihai G; Kullberg, Bart-Jan

    2016-01-01

    Differentiating between inflammatory disorders is difficult, but important for a rational use of antimicrobial agents. Biomarkers reflecting the host immune response may offer an attractive strategy to predict the etiology of an inflammatory process and can thus be of help in decision making. We performed a review of the literature to evaluate the diagnostic value of inflammatory biomarkers in adult patients admitted to the hospital with suspected systemic acute infections. Elevated procalcitonin (PCT) concentrations indicate a bacterial infection in febrile patients with an auto-immune disease, rather than a disease flare. CD64 expression on neutrophils can discriminate between non-infectious systemic inflammation and sepsis, and limited evidence suggests the same for decoy receptor 3. PCT is useful for both diagnosing bacterial infection complicating influenza and guiding antibiotic treatment in lower respiratory tract infections in general. In undifferentiated illnesses, increased CD35 expression on neutrophils distinguishes bacterial from viral infections. Compared to bacterial infections, invasive fungal infections are characterized by low concentrations of PCT. No biomarker predicting a specific infecting agent could be identified. PMID:26429736

  20. PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

    PubMed

    Wang, Hong-Mei; Zhao, Yan-Xin; Zhang, Shi; Liu, Gui-Dong; Kang, Wen-Yan; Tang, Hui-Dong; Ding, Jian-Qing; Chen, Sheng-Di

    2010-01-01

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes. PMID:20413894

  1. Lancemaside A from Codonopsis lanceolata modulates the inflammatory responses mediated by monocytes and macrophages.

    PubMed

    Kim, Eunji; Yang, Woo Seok; Kim, Ji Hye; Park, Jae Gwang; Kim, Han Gyung; Ko, Jaeyoung; Hong, Yong Deog; Rho, Ho Sik; Shin, Song Seok; Sung, Gi-Ho; Cho, Jae Youl

    2014-01-01

    In this study, we aimed to examine the cellular and molecular mechanisms of lancemaside A from Codonopsis lanceolata (Campanulaceae) in the inflammatory responses of monocytes (U937 cells) and macrophages (RAW264.7 cells). Lancemaside A significantly suppressed the inflammatory functions of lipopolysaccharide- (LPS-) treated RAW264.7 cells by suppressing the production of nitric oxide (NO), the expression of the NO-producing enzyme inducible NO synthase (iNOS), the upregulation of the costimulatory molecule CD80, and the morphological changes induced by LPS exposure. In addition, lancemaside A diminished the phagocytic activity of RAW264.7 cells and boosted the neutralizing capacity of these cells when treated with the radical generator sodium nitroprusside (SNP). Interestingly, lancemaside A strongly blocked the adhesion activity of RAW264.7 cells to plastic culture plates, inhibited the cell-cell and cell-fibronectin (FN) adhesion of U937 cells that was triggered by treatment with an anti-β1-integrin (CD29) antibody and immobilized FN, respectively. By evaluating the activation of various intracellular signaling pathways and the levels of related nuclear transcription factors, lancemaside A was found to block the activation of inhibitor of κB kinase (IKK) and p65/nuclear factor- (NF-) κB. Taken together, our findings strongly suggest that the anti-inflammatory function of lancemaside A is the result of its strong antioxidative and IKK/NF-κB inhibitory activities. PMID:24782593

  2. Mutation of cysteine 46 in IKK-beta increases inflammatory responses.

    PubMed

    Li, Ting; Wong, Vincent Kam Wai; Jiang, Zhi Hong; Jiang, Shui Ping; Liu, Yan; Wang, Ting Yu; Yao, Xiao Jun; Su, Xiao Hui; Yan, Feng Gen; Liu, Juan; Leung, Elaine Lai-Han; Yi, Xiao Qin; Wong, Yuen Fan; Zhou, Hua; Liu, Liang

    2015-10-13

    Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β-NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-β C46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-β C46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-β. PMID:26378659

  3. Thioredoxin-1 Increases Survival in Sepsis by Inflammatory Response Through Suppressing Endoplasmic Reticulum Stress.

    PubMed

    Chen, Guobing; Li, Xiang; Huang, Mengbing; Li, Mei; Zhou, Xiaoshuang; Li, Ye; Bai, Jie

    2016-07-01

    Sepsis is the main cause of death in critically ill patients, pathogenesis of which is still unclear. The nuclear factor κB (NF-κB) inflammatory signal pathway mediated by endoplasmic reticulum stress is involved in sepsis. Thioredoxin-1 (Trx-1) is an important protein of regulating oxidative stress. It plays a crucial role in the anti-oxidation, anti-apoptosis, and anti-inflammation. However, the role and the mechanism of Trx-1 in sepsis have not been extensively studied. In the present study, we showed that the survival was longer in sepsis induced by cecal ligation and puncture in Trx-1 overexpression transgenic (Tg) mice compared with wild-type mice. Wet/dry lung weight ratio was decreased in Trx-1 Tg mice. The levels of TNF-α and IL-1β in plasma and lung tissue were inhibited in Tg mice. The expressions of glucose-regulated protein 78, inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2, C/EBP homologous protein, NF-κB, and inhibitors of NF-κBα were increased in lung tissue. More importantly, the overexpression of Trx-1 in transgenic mice suppressed NF-κB inflammatory signal pathway by inhibiting the activation of molecules involved in ER stress. Our results suggest that Trx-1 may play protective role in extending survival in sepsis by regulating inflammatory response through suppressing ER stress. PMID:27299588

  4. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  5. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2015-11-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  6. Withaferin A inhibits inflammatory responses induced by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages.

    PubMed

    Noh, Eui-Jeong; Kang, Ming-Jung; Jeong, Yu-Jin; Lee, Jun-Young; Park, Jung-Hwan; Choi, Hye-Jin; Oh, Sang-Muk; Lee, Kyung-Bok; Kim, Dong-Jae; Shin, Ji-Ae; Cho, Sung-Dae; Park, Jong-Hwan

    2016-07-01

    Periodontitis is a progressive chronic inflammatory disease and a major cause of tooth loss in humans. As a withanolides, withaferin A (WA) is known to exhibit strong anti‑inflammatory activity. The present study examined whether WA inhibited inflammatory responses in macrophages in response to two representative periodontal pathogens, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans. Murine bone marrow‑derived macrophages (BMDMs) were used in this study and cytokine production in culture supernatants was measured by enzyme‑linked immunosorbent assays. Western blot analysis was performed to determine the activation of nuclear factor‑κB and mitogen‑activated protein kinases (MAPKs) and the expression of inducible nitric oxide synthase (iNOS), toll‑like receptor (TLR) 2 and TLR4. The production of nitric oxide (NO) was determined by the Griess reaction. WA treatment was shown to decrease interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α production in BMDMs in response to F. nucleatum and A. actinomycetemcomitans in a dose‑dependent manner. The phosphorylation of IκB‑α and MAPKs (p38, extracellular signal‑regulated kinases and c‑Jun N‑terminal kinases) induced by F. nucleatum and A. actinomycetemcomitans was also inhibited by WA. F. nucleatum and A. actinomycetemcomitans induced iNOS expression and NO production in BMDMs, which was inhibited by WA in a dose‑dependent manner. WA also reduced endogenous and induced expression of TLR2 and TLR4 in these cells. These results suggest that WA may be a potential therapeutic agent or preventive additive for periodontitis control. PMID:27220676

  7. Preventively enteral application of immunoglobulin enriched colostrums milk can modulate postoperative inflammatory response

    PubMed Central

    2013-01-01

    Several studies demonstrated acute inflammatory response following traumatic injury. Inflammatory response during surgical interventions was verified by a significant increase of endotoxin plasma levels and a decrease of the endotoxin neutralizing capacity (ENC). However, the incidence of elevated endotoxin levels was significantly higher (89%) than detected bacterial translocation (35%). Thus parts or products of Gram-negative bacteria seem to translocate more easily into the blood circulation than whole bacteria. Along with the bacterial translocation, the inflammatory response correlated directly with the severity of the surgical intervention. In comparison after major and minor surgery Interleukin-6 (IL-6) and C-reactive protein (CRP) was also significantly different. Similar effects in mediator release were shown during endovascular stent graft placement and open surgery in infrarenal aortic aneurysm. Open surgery demonstrated a significant stronger endotoxin translocation and a decrease of ENC. Strategies to prevent translocation seem to be sensible. Colostrum is the first milk produced by the mammary glands within the first days after birth. It contains a complex system of immune factors and has a long history of use in traditional medicine. Placebo-controlled studies verified that prophylactic oral application of immunoglobulin-enriched colostrum milk preparation diminishes perioperative endotoxemia, prevents reduction of ENC and reduces postoperative CRP-levels, suggesting a stabilization of the gut barrier. This effect may be caused by immunoglobulin transportation by the neonatal receptor FcRn of the mucosal epithelium. In conclusion, there is an association of perioperative endotoxemia and the subsequent increase in mediators of the acute phase reaction in surgical patients. A prophylactic oral application of colostrum milk is likely to stabilize the gut barrier i.e. reduces the influx of lipopolysaccharides arising from Gram-negative bacterial

  8. Preventively enteral application of immunoglobulin enriched colostrums milk can modulate postoperative inflammatory response.

    PubMed

    Orth, Klaus; Knoefel, Wolfram Trudo; van Griensven, Martijn; Matuschek, Christiane; Peiper, Matthias; Schrumpf, Holger; Gerber, Peter Arne; Budach, Wilfried; Bölke, Edwin; Buhren, Bettina Alexandra; Schauer, Matthias

    2013-01-01

    Several studies demonstrated acute inflammatory response following traumatic injury. Inflammatory response during surgical interventions was verified by a significant increase of endotoxin plasma levels and a decrease of the endotoxin neutralizing capacity (ENC). However, the incidence of elevated endotoxin levels was significantly higher (89%) than detected bacterial translocation (35%). Thus parts or products of Gram-negative bacteria seem to translocate more easily into the blood circulation than whole bacteria. Along with the bacterial translocation, the inflammatory response correlated directly with the severity of the surgical intervention. In comparison after major and minor surgery Interleukin-6 (IL-6) and C-reactive protein (CRP) was also significantly different. Similar effects in mediator release were shown during endovascular stent graft placement and open surgery in infrarenal aortic aneurysm. Open surgery demonstrated a significant stronger endotoxin translocation and a decrease of ENC. Strategies to prevent translocation seem to be sensible. Colostrum is the first milk produced by the mammary glands within the first days after birth. It contains a complex system of immune factors and has a long history of use in traditional medicine. Placebo-controlled studies verified that prophylactic oral application of immunoglobulin-enriched colostrum milk preparation diminishes perioperative endotoxemia, prevents reduction of ENC and reduces postoperative CRP-levels, suggesting a stabilization of the gut barrier. This effect may be caused by immunoglobulin transportation by the neonatal receptor FcRn of the mucosal epithelium.In conclusion, there is an association of perioperative endotoxemia and the subsequent increase in mediators of the acute phase reaction in surgical patients. A prophylactic oral application of colostrum milk is likely to stabilize the gut barrier i.e. reduces the influx of lipopolysaccharides arising from Gram-negative bacterial pathogens

  9. Oleanolic Acid Controls Allergic and Inflammatory Responses in Experimental Allergic Conjunctivitis

    PubMed Central

    Martínez-García, Carmen; Martín, Rubén; Gallego-Muñoz, Patricia; Hernández, Marita; Nieto, María L.

    2014-01-01

    Pollen is the most common aeroallergen to cause seasonal conjunctivitis. The result of allergen exposure is a strong Th2-mediated response along with conjunctival mast cell degranulation and eosinophilic infiltration. Oleanolic acid (OA) is natural a triterpene that displays strong anti-inflammatory and immunomodulatory properties being an active anti-allergic molecule on hypersensitivity reaction models. However, its effect on inflammatory ocular disorders including conjunctivits, has not yet been addressed. Hence, using a Ragweed pollen (RWP)-specific allergic conjunctivitis (EAC) mouse model we study here whether OA could modify responses associated to allergic processes. We found that OA treatment restricted mast cell degranulation and infiltration of eosinophils in conjunctival tissue and decreased allergen-specific Igs levels in EAC mice. Th2-type cytokines, secreted phospholipase A2 type-IIA (sPLA2-IIA), and chemokines levels were also significantly diminished in the conjunctiva and serum of OA-treated EAC mice. Moreover, OA treatment also suppressed RWP-specific T-cell proliferation. In vitro studies, on relevant cells of the allergic process, revealed that OA reduced the proliferative and migratory response, as well as the synthesis of proinflammatory mediators on EoL-1 eosinophils and RBL-2H3 mast cells exposed to allergic and/or crucial inflammatory stimuli such as RWP, sPLA2-IIA or eotaxin. Taken together, these findings demonstrate the beneficial activity of OA in ocular allergic processes and may provide a new intervention strategy and potential therapy for allergic diseases. PMID:24699261

  10. Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

    PubMed Central

    Rubio-Ruiz, María Esther; Pérez-Torres, Israel; Diaz-Diaz, Eulises; Pavón, Natalia; Guarner-Lans, Verónica

    2014-01-01

    Aim: Metabolic syndrome (MS) and aging are low-grade systemic inflammatory conditions, and inflammation is a key component of endothelial dysfunction. The aim of this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) upon the vascular reactivity in aging MS rats. Methods: MS was induced in young male rats by adding 30% sucrose in drinking water over 6, 12, and 18 months. When the treatment was finished, the blood samples were collected, and aortas were dissected out. The expression of COX isoenzymes and PLA2 in the aortas was analyzed using Western blot analysis. The contractile responses of aortic rings to norepinephrine (1 μmol/L) were measured in the presence or absence of different NSAIDs (10 μmol/L for each). Results: Serum levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in control rats were remained stable during the aging process, whereas serum IL-6 in MS rats were significantly increased at 12 and 18 months. The levels of COX isoenzyme and PLA2 in aortas from control rats increased with the aging, whereas those in aortas from MS rats were irregularly increased with the highest levels at 6 months. Pretreatment with acetylsalicylic acid (a COX-1 preferential inhibitor), indomethacin (a non-selective COX inhibitor) or meloxicam (a COX-2 preferential inhibitor) decreased NE-induced contractions of aortic rings from MS rats at all the ages, with meloxicam being the most potent. Acetylsalicylic acid also significantly reduced the maximum responses of ACh-induced vasorelaxation of aortic rings from MS rats, but indomethacin and meloxicam had no effect. Conclusion: NSAIDs can directly affect vascular responses in aging MS rats. Understanding the effects of NSAIDs on blood vessels may improve the treatment of cardiovascular diseases and MS in the elders. PMID:25263337

  11. Cardiopulmonary Bypass Down-Regulates NOD Signaling and Inflammatory Response in Children with Congenital Heart Disease.

    PubMed

    Yang, Qinghua; Liao, Jianyi; Huang, Jie; Li, Yi Ping; Huang, Shungen; Zhou, Huiting; Xie, Yi; Pan, Jian; Li, Yanhong; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatory cytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients. PMID:27622570

  12. Effects of trace element supplementation on the inflammatory response in a rabbit model of major trauma.

    PubMed

    Yuan, Wan-an; Yu, Xiao-jun; Liu, Fu-Qi; Wang, Hai-peng; Wang, Dian; Lai, Xiao-ping

    2010-01-01

    Patients with a severe trauma exhibit a strong oxidative stress, an intense inflammatory response, and long-lasting hypermetabolism, all of which are proportional to the severity of injury. In this study, we investigated the impact of trace element (TE) supplementation on the inflammatory response in an animal model of major trauma. New Zealand White rabbits were randomly assigned as a control group (n=5) and an experimental group (n=70) that, after receiving a major trauma, was subdivided into Trauma-Control (n=35) and Trauma-TE (n=35) groups. Systemic inflammatory response syndrome (SIRS) was observed in 40 out of 70 rabbits with a trauma, with a higher incidence in the Trauma-Control group (88.6%; 31/35) than the Trauma-TE group (28.6%; 10/35) (p<0.01). The mortality rate was significantly different between the Trauma-Control and the Trauma-TE groups; (34% vs. 8%; p<0.01). There were significant post-trauma alterations in the levels of (1) serum and spleen zinc (Zn), copper (Cu), selenium (Se), and manganese (Mn), (2) serum AST and ALT, (3) serum interleukin-6/10, and (4) nuclear factor kappa binding (NF-kappaB) activity and the expression. TE supplementation: (1) improved blood urea nitrogen (BUN), and creatinine (Cr) levels, (2) stabilized IL-6/10 production, (3) decreased NF-kappaB p(65) production. Appropriate TE supplementation can improve the TE status, mitigate SIRS, and reduce the mortality due to multiple organ dysfunction syndromes (MODS)/multiple organ failure (MOF) after major trauma. PMID:20122578

  13. Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise

    PubMed Central

    Dennis, Richard A; Trappe, Todd A; Simpson, Pippa; Carroll, Chad; Emma Huang, B; Nagarajan, Radhakrishnan; Bearden, Edward; Gurley, Cathy; Duff, Gordon W; Evans, William J; Kornman, Kenneth; Peterson, Charlotte A

    2004-01-01

    Inflammation appears to play an important role in the repair and regeneration of skeletal muscle after damage. We tested the hypothesis that the severity of the inflammatory response in muscle after an acute bout of resistance exercise is associated with single nucleotide polymorphisms (SNPs) previously shown to alter interleukin-1 (IL-1) activity. Using a double-blind prospective design, sedentary young men were screened (n = 100) for enrolment (n = 24) based upon having 1 of 4 haplotype patterns composed of five polymorphic sites in the IL-1 gene cluster: IL-1A (+4845), IL-1B (+3954), IL-1B (−511), IL-1B (−3737) and IL-1RN (+2018). Subjects performed a standard bout of resistance leg exercise and vastus lateralis biopsies were obtained pre-, and at 24, and 72 h post-exercise. Inflammatory marker mRNAs (IL-1β, IL-6 and tumor necrosis factor-α (TNF-α)) and the number of CD68+ macrophages were quantified. Considerable variation was observed in the expression of these gene products between subjects. At 72 h post-exercise, IL-1β had increased in a number of subjects (n = 10) and decreased (n = 4) or did not change (n = 10) in others. Inflammatory responses were significantly associated with specific haplotype patterns and were also influenced by individual SNPs. Subjects with genotypes 1.1 at IL-1B (+3954) or 2.2 at IL-1B (−3737) had approximately a 2-fold higher median induction of several markers, but no increase in macrophages, suggesting that cytokine gene expression is elevated per macrophage. The IL-1RN (+2018) SNP maximized the response specifically within these groups and was associated with increased macrophage recruitment. This is the first report that IL-1 genotype is associated with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise. PMID:15331687

  14. Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease

    PubMed Central

    Thome, Aaron D.; Standaert, David G.; Harms, Ashley S.

    2015-01-01

    Background Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer’s disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation. Methods To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn. Results We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn. Conclusion Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD. PMID:26469270

  15. ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland

    PubMed Central

    Wang, Ching-Shuen; Wee, Yinshen; Yang, Chieh-Hsiang; Melvin, James E.; Baker, Olga J.

    2016-01-01

    Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A4 and resolvin D1 (RvD1) promotes resolution of inflammation. Our previous in vitro studies indicate that RvD1 activation of ALX/FPR2 resolves cytokine-mediated inflammatory responses in mammalian cells. However, the impact of ALX/FPR2 activation on salivary gland function in vivo is unknown. The objective of this study was to determine whether submandibular glands (SMG) from ALX/FPR2−/− mice display enhanced inflammatory responses to lipopolysaccharides (LPS) stimulation. For these studies, C57BL/6 and ALX/FPR2−/− mice at age 8-12-week-old were treated with LPS by i.p for 24 h. Salivary gland structure and function were analyzed by histopathological assessment, saliva flow rate, quantitative PCR, Western blot analyses and immunofluorescence. Our results showed the following events in the ALX/FPR2−/− mice treated with LPS: a) upregulated inflammatory cytokines and decreased M3R (Muscarinic Acetylcholine receptor M3) and AQP5 (Aquaporin 5) protein expression, b) decreased saliva secretion, c) increased apoptosis, d) alteration of tight junction and neuronal damage. Overall, our data suggest that the loss of ALX/FPR2 results in unresolved acute inflammation and SMG dysfunction (xerostomia) in response to LPS that is similar to human salivary gland dysfunction induced by bacterial infection. PMID:27064029

  16. Relationship between sympathetic nervous activity and inflammatory response after subarachnoid hemorrhage in a perforating canine model.

    PubMed

    Gao, Cheng; Liu, Xiangzhen; Shi, Huaizhang; Xu, Shancai; Ji, Zhiyong; Wang, Chunlei; Wu, Pei; Liu, Zhen; Zhao, Shiguang

    2009-05-11

    The objective of the present study was to evaluate the correlation between sympathetic nerve activation and inflammatory response in the acute stage of subarachnoid hemorrhage (SAH) in a canine perforating model. SAH was induced by perforation of the basilar artery with the use of a microcatheter via the femoral artery in 20 mongrel dogs. Hemodynamic parameters and intracranial pressure were recorded, and blood sample for C3a, C5b-9, IL-6, IL-8 and noradrenaline kinetic determination were measured at 0, 5, 15, 30, 60, 120, and 180 min after SAH. Noradrenaline (pg/mL) increased abruptly from 104+/-59 to 2010+/-918 at 5 min after SAH. C3a and C5b-9 reached peak values at 15 min and IL-6 and IL-8 reached peak values at 30 min after SAH, respectively. The peak values of C3a and C5b-9 correlated positively with the peak value of noradrenaline (r=0.743 and r=0.753, respectively). The peak values of IL-6 and IL-8 also correlated positively with the peak values of noradrenaline (r=0.603 and r=0.681, respectively).These results suggest that a pronounced activation of the sympathetic nervous system and the inflammatory response occurs in acute stage of SAH. Significant association between the rate of spillover of norepinephrine to plasma and the plasma levels of inflammatory markers indicates that the two processes, sympathetic activation and immune response are quantitatively linked in early stage after SAH. The exact mechanisms underlying this phenomenon deserved further investigations. PMID:19217831

  17. Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease.

    PubMed

    Marín, Alicia C; Gisbert, Javier P; Chaparro, María

    2015-10-28

    Inflammatory bowel disease (IBD) is an immunological disorder that is usually treated with immunosuppressive therapy, potentially leading to increases in vulnerability to infections. Although many infections can be prevented by vaccination, vaccination coverage in these patients in clinical practice is insufficient. Therefore, the seroprotection condition should be verified, even for routine vaccines, such as hepatitis B or pneumococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B, influenza, and pneumococcal vaccines is impaired in IBD patients, whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand, data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella, varicella, and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response, specifically to vaccines, in patients with immune-mediated diseases (such as IBD), is crucial when developing vaccines that trigger more potent immunologic responses. PMID:26527572

  18. Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease

    PubMed Central

    Marín, Alicia C; Gisbert, Javier P; Chaparro, María

    2015-01-01

    Inflammatory bowel disease (IBD) is an immunological disorder that is usually treated with immunosuppressive therapy, potentially leading to increases in vulnerability to infections. Although many infections can be prevented by vaccination, vaccination coverage in these patients in clinical practice is insufficient. Therefore, the seroprotection condition should be verified, even for routine vaccines, such as hepatitis B or pneumococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B, influenza, and pneumococcal vaccines is impaired in IBD patients, whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand, data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella, varicella, and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response, specifically to vaccines, in patients with immune-mediated diseases (such as IBD), is crucial when developing vaccines that trigger more potent immunologic responses. PMID:26527572

  19. Inorganic arsenic exposure affects pain behavior and inflammatory response in rat

    SciTech Connect

    Aguirre-Banuelos, Patricia; Escudero-Lourdes, Claudia; Sanchez-Pena, Luz Carmen; Del Razo, Luz Maria; Perez-Urizar, Jose

    2008-06-15

    Inorganic arsenic (iAs) contamination of drinking water is a worldwide problem associated with an increased risk for the development of various types of cancer and noncancerous damage. In vitro studies have suggested that iAs can modulate the activity of macrophages producing an over-expression of cyclooxygenase-2 (COX-2) and resulting in an increase in prostaglandin E{sub 2} (PGE{sub 2}) concentrations in endothelial cells. These effects may lead to an in vivo enhancement of inflammatory and pain responses. Our aim was to determine the effect of a single dose of arsenic or subchronic exposure to arsenic on pain behavior and tissue inflammation in rats. Rats were given a single dose of sodium arsenite (0.1, 1 and 10 mg/kg i.p.) or submitted to subchronic exposure to arsenic added to the drinking water for 4 weeks (0.1, 1, 10 and 100 ppm). Inflammatory pain was assessed by using the formalin and tail-flick tests, while inflammation was evaluated with the carrageenan model. Arsenite did not induce pain or significant inflammation by itself. In contrast, arsenite in both single dose administration and subchronic exposure increased not only the inflammatory process and the underlying hyperalgesic pain, but also induced a decrease in the pain threshold. Alterations in pain processing were dependent on the arsenic dose and the length of exposure, and the underlying mechanism involved an increased release of local PGE{sub 2}. These results suggest that inorganic arsenic exposure enhances pain perception and exacerbates the pathological state of inflammatory diseases.

  20. Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model

    PubMed Central

    LU, WEI; WANG, LIN; WO, CHUNXIN; YAO, JING

    2016-01-01

    The aim of the present study was to investigate the efficacy of ketamine in attenuating osteoarthritis (OA) and modulating the expression of inflammatory mediators. A rabbit OA model was established by knee immobilization using plaster bandages. After six weeks, rabbits were randomly allocated into four groups (n=6/group): Normal saline, Ket60, Ket100, and Ket200 and twice a week for four weeks the rabbits received an intra-articular injection of saline, or 60, 100 or 200 µmol/l ketamine, respectively. One week after the final injection, samples of synovial membrane, synovial fluid and articular cartilage were isolated. The pathological changes were assessed by general observation, hematoxylin and eosin staining and Alcian blue/periodic-acid Schiff staining. Cartilage pathology was assessed using Mankin's scoring system. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 levels in the synovial fluid were measured by enzyme-linked immunosorbent assays. The nuclear factor (NF)-κB p65 subunit expression level in cartilage samples was determined by immunohistochemistry. OA was characterized by morphological changes in the articular surface, cartilage lesions, infiltration of inflammatory cells and a significantly increased Mankin's score. Elevated TNF-α and reduced IL-10 levels in the synovial fluid, along with increased p65 expression levels in the cartilage were observed in OA rabbits. Intra-articular injection of ketamine ameliorated the pathological characteristics of OA, reduced the Mankin's score, decreased TNF-α and NF-κB p65 expression levels, and increased the level of IL-10 expression in a dose-dependent manner. Thus is was demonstrated that Ketamine suppresses the inflammatory response in OA by modulating inflammatory mediator expression levels in a rabbit model of OA. PMID:27109206

  1. Using magnetic resonance imaging to quantify the inflammatory response following allergen challenge in allergic rhinitis.

    PubMed

    Leaker, Brian R; Scadding, Glenis; Jones, C Richard; Barnes, Peter J

    2015-12-01

    Current rhinometric and flow assessments measure nasal patency and are often poorly correlated with rhinitis symptoms. To evaluate magnetic resonance imaging (MRI) as a new method to measure inflammatory changes in nasal and sinus mucosa following nasal allergen challenge. A pilot study (n = 6) determined the optimal technical settings for MRI to measure inflammatory change which were then adopted for the main study. This study was a single blind, placebo-controlled, three-way crossover trial in 14 subjects with seasonal allergic rhinitis. Effects of cetirizine, cetirizine and pseudoephedrine (Cet+PE), or placebo on total nasal symptom scores (TNSS), peak nasal inspiratory flow (PNIF), nasal nitric oxide (nNO), acoustic rhinometry, and MRI end points following nasal intranasal allergen challenge were measured. There were significant changes in all parameters after allergen challenge (P < 0.01), except for nNO. MRI end points were less variable and more consistent than PNIF and acoustic rhinometry in detecting changes after allergen challenge. Total nasal airspace volume was the most sensitive and reproducible MRI measurement, with a mean reduction from -5.37 cm(3) (95%CI -7.35, -3.38; P < 0.001), which was maximal 60 min after allergen challenge. A change of one in TNSS corresponded to a change in MRI volume of -0.57 cm(3). There was an improvement in all parameters (except nNO) in subjects taking Cet+PE compared with placebo, however this did not achieve significance probably because of the small study size (overall analysis P > 0.07; comparison of active versus placebo P > 0.09). MRI provides novel insights into the anatomical inflammatory changes post allergen challenge and provides a new method for assessment of nasal patency and objective measurement of inflammatory responses. PMID:26733348

  2. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction

    PubMed Central

    Dobaczewski, Marcin; Gonzalez-Quesada, Carlos; Frangogiannis, Nikolaos G

    2009-01-01

    The dynamic alterations in the cardiac extracellular matrix following myocardial infarction not only determine the mechanical properties of the infarcted heart, but also directly modulate the inflammatory and reparative response. During the inflammatory phase of healing, rapid activation of matrix metalloproteinases (MMP) causes degradation of the cardiac extracellular matrix. Matrix fragments exert potent pro-inflammatory actions, while MMPs process cytokines and chemokines altering their biological activity. In addition, vascular hyperpermeability results in extravasation of fibronectin and fibrinogen leading to formation of a plasma-derived provisional matrix that serves as a scaffold for leukocyte infiltration. Clearance of the infarct from dead cells and matrix debris is essential for resolution of inflammation and marks the transition to the proliferative phase. The fibrin-based provisional matrix is lysed and cellular fibronectin is secreted. ED-A fibronectin, mechanical tension and Transforming Growth Factor (TGF)-β are essential for modulation of fibroblasts into myofibroblasts, the main collagen-secreting cells in the wound. The matricellular proteins thrombospondin-1 and -2, osteopontin, tenascin-C, periostin, and secreted protein acidic and rich in cysteine (SPARC) are induced in the infarct regulating cellular interactions and promoting matrix organization. As the infarct matures, matrix cross-linking results in formation of a dense collagen-based scar. At this stage, shielding of fibroblasts from external mechanical tension by the mature matrix network may promote deactivation and cellular quiescence. The components of the extracellular matrix do not passively follow the pathologic alterations of the infarcted heart but critically modulate inflammatory and reparative pathways by transducing signals that affect cell survival, phenotype and gene expression. PMID:19631653

  3. Environmental Particulate Matter Induces Murine Intestinal Inflammatory Responses and Alters the Gut Microbiome

    PubMed Central

    Kish, Lisa; Hotte, Naomi; Kaplan, Gilaad G.; Vincent, Renaud; Tso, Robert; Gänzle, Michael; Rioux, Kevin P.; Thiesen, Aducio; Barkema, Herman W.; Wine, Eytan; Madsen, Karen L.

    2013-01-01

    Background Particulate matter (PM) is a key pollutant in ambient air that has been associated with negative health conditions in urban environments. The aim of this study was to examine the effects of orally administered PM on the gut microbiome and immune function under normal and inflammatory conditions. Methods Wild-type 129/SvEv mice were gavaged with Ottawa urban PM10 (EHC-93) for 7–14 days and mucosal gene expression analyzed using Ingenuity Pathways software. Intestinal permeability was measured by lactulose/mannitol excretion in urine. At sacrifice, segments of small and large intestine were cultured and cytokine secretion measured. Splenocytes were isolated and incubated with PM10 for measurement of proliferation. Long-term effects of exposure (35 days) on intestinal cytokine expression were measured in wild-type and IL-10 deficient (IL-10−/−) mice. Microbial composition of stool samples was assessed using terminal restriction fragment length polymorphism. Short chain fatty acids were measured in caecum. Results Short-term treatment of wild-type mice with PM10 altered immune gene expression, enhanced pro-inflammatory cytokine secretion in the small intestine, increased gut permeability, and induced hyporesponsiveness in splenocytes. Long-term treatment of wild-type and IL-10−/− mice increased pro-inflammatory cytokine expression in the colon and altered short chain fatty acid concentrations and microbial composition. IL-10−/− mice had increased disease as evidenced by enhanced histological damage. Conclusions Ingestion of airborne particulate matter alters the gut microbiome and induces acute and chronic inflammatory responses in the intestine. PMID:23638009

  4. Oxidative effects on lung inflammatory response in rats exposed to different concentrations of formaldehyde.

    PubMed

    Murta, Giselle Luciane; Campos, Keila Karine Duarte; Bandeira, Ana Carla Balthar; Diniz, Mirla Fiuza; Costa, Guilherme de Paula; Costa, Daniela Caldeira; Talvani, André; Lima, Wanderson Geraldo; Bezerra, Frank Silva

    2016-04-01

    The formaldehyde (FA) is a crosslinking agent that reacts with cellular macromolecules such as proteins, nucleic acids and molecules with low molecular weight such as amino acids, and it has been linked to inflammatory processes and oxidative stress. This study aimed to analyze the oxidative effects on pulmonary inflammatory response in Fischer rats exposed to different concentrations of FA. Twenty-eight Fischer rats were divided into 4 groups (N = 7). The control group (CG) was exposed to ambient air and three groups were exposed to different concentrations of FA: 1% (FA1%), 5% (FA5%) and 10% (FA10%). In the Bronchoalveolar Lavage Fluid (BALF), the exposure to a concentration of 10% promoted the increase of inflammatory cells compared to CG. There was also an increase of macrophages and lymphocytes in FA10% and lymphocytes in FA5% compared to CG. The activity of NADPH oxidase in the blood had been higher in FA5% and FA10% compared to CG. The activity of superoxide dismutase enzyme (SOD) had an increase in FA5% and the activity of the catalase enzyme (CAT) showed an increase in FA1% compared to CG. As for the glutathione system, there was an increase in total glutathione (tGSH), reduced glutathione (GSH) and oxidized glutathione (GSSG) in FA5% compared to CG. The reduced/oxidized glutathione ratio (GSH/GSSG) had a decrease in FA5% compared to CG. There was an increase in lipid peroxidation compared to all groups and the protein carbonyl formation in FA10% compared to CG. We also observed an increase in CCL2 and CCL5 chemokines in the treatment groups compared to CG and in serum there was an increase in CCL2, CCL3 and CCL5 compared to CG. Our results point out to the potential of formaldehyde in promoting airway injury by increasing the inflammatory process as well as by the redox imbalance. PMID:26774767

  5. Equine herpesvirus type 1 modulates inflammatory host immune response genes in equine endothelial cells.

    PubMed

    Johnstone, Stephanie; Barsova, Jekaterina; Campos, Isabel; Frampton, Arthur R

    2016-08-30

    Equine herpesvirus myeloencephalopathy (EHM), a disease caused by equine herpesvirus type 1 (EHV-1), is characterized by severe inflammation, thrombosis, and hypoxia in central nervous system (CNS) endothelial cells, which can result in a spectrum of clinical signs including urinary incontinence, ataxia, and paralysis. Strains of EHV-1 that contain a single point mutation within the viral DNA polymerase (nucleotide A2254>G2254: amino acid N752→D752) are isolated from EHM afflicted horses at higher frequencies than EHV-1 strains that do not harbor this mutation. Due to the correlation between the DNA Pol mutation and EHM disease, EHV-1 strains that contain the mutation have been designated as neurologic. In this study, we measured virus replication, cell to cell spread efficacy, and host inflammatory responses in equine endothelial cells infected with 12 different strains of EHV-1. Two strains, T953 (Ohio 2003) (neurologic) and Kentucky A (KyA) (non-neurologic), have well described disease phenotypes while the remaining strains used in this study are classified as neurologic or non-neurologic based solely on the presence or absence of the DNA pol mutation, respectively. Results show that the neurologic strains do not replicate better or spread more efficiently in endothelial cells. Also, the majority of the host inflammatory genes were modulated similarly regardless of EHV-1 genotype. Analyses of host gene expression showed that a subset of pro-inflammatory cytokines, including the CXCR3 ligands CXCL9, CXCL10, and CXCL11, as well as CCL5, IL-6 and TNF-α were consistently up-regulated in endothelial cells infected with each EHV-1 strain. The identification of specific pro-inflammatory cytokines in endothelial cells that are modulated by EHV-1 provides further insight into the factors that contribute to the immunopathology observed after infection and may also reveal new targets for disease intervention. PMID:27527764

  6. Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies

    PubMed Central

    Codolo, Gaia; Plotegher, Nicoletta; Pozzobon, Tommaso; Brucale, Marco; Tessari, Isabella; Bubacco, Luigi; de Bernard, Marina

    2013-01-01

    Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar α-synuclein (αSyn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD. PMID:23383169

  7. Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model.

    PubMed

    Lu, Wei; Wang, Lin; Wo, Chunxin; Yao, Jing

    2016-06-01

    The aim of the present study was to investigate the efficacy of ketamine in attenuating osteoarthritis (OA) and modulating the expression of inflammatory mediators. A rabbit OA model was established by knee immobilization using plaster bandages. After six weeks, rabbits were randomly allocated into four groups (n=6/group): Normal saline, Ket60, Ket100, and Ket200 and twice a week for four weeks the rabbits received an intra‑articular injection of saline, or 60, 100 or 200 µmol/l ketamine, respectively. One week after the final injection, samples of synovial membrane, synovial fluid and articular cartilage were isolated. The pathological changes were assessed by general observation, hematoxylin and eosin staining and Alcian blue/periodic‑acid Schiff staining. Cartilage pathology was assessed using Mankin's scoring system. Tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 levels in the synovial fluid were measured by enzyme‑linked immunosorbent assays. The nuclear factor (NF)‑κB p65 subunit expression level in cartilage samples was determined by immunohistochemistry. OA was characterized by morphological changes in the articular surface, cartilage lesions, infiltration of inflammatory cells and a significantly increased Mankin's score. Elevated TNF‑α and reduced IL-10 levels in the synovial fluid, along with increased p65 expression levels in the cartilage were observed in OA rabbits. Intra‑articular injection of ketamine ameliorated the pathological characteristics of OA, reduced the Mankin's score, decreased TNF‑α and NF‑κB p65 expression levels, and increased the level of IL‑10 expression in a dose-dependent manner. Thus is was demonstrated that Ketamine suppresses the inflammatory response in OA by modulating inflammatory mediator expression levels in a rabbit model of OA. PMID:27109206

  8. IκBζ Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.

    PubMed

    Sundaram, Kruthika; Rahman, Mohd Akhlakur; Mitra, Srabani; Knoell, Daren L; Woodiga, Shireen A; King, Samantha J; Wewers, Mark D

    2016-01-01

    Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced IκBζ in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, IκBζ knockdown reduced the expression of IL-6 and GMCSF. Furthermore, IκBζ overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced IκBζ. While inhibition of TLR1/TLR2 blocked D39 induced IκBζ expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NFκB suppressed D39 induced IκBζ. Overall, our data demonstrates that IκBζ regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF. PMID:27597997

  9. Antibody and inflammatory responses in laying hens with experimental primary infections of Ascaridia galli.

    PubMed

    Marcos-Atxutegi, C; Gandolfi, B; Arangüena, T; Sepúlveda, R; Arévalo, M; Simón, F

    2009-04-01

    Ascaridia galli, an intestinal nematode that affects hens and other domestic and wild birds, causes economic losses in avian exploitations. The present work shows that A. galli stimulates a strong antibody response as well as an intense inflammatory reaction, in the intestinal mucous of experimentally infected Lohmann Brown laying hens. IgG antibodies against soluble extracts of A. galli embrionated eggs and adult worms, were detected in both blood and yolks eggs from infected hens during a period of 105 days after the infection. This indicates that hens transfer to their offspring a part of the IgG antibodies produced when they become infected. The antigens responsible for the stimulation of specific IgG were molecules of 30-34, 44-54 and 58-90 kDa, while in the yolk eggs of infected hens a reactivity directed against antigens of molecular weight (M(w)) lower than 50 kDa was detected. Histology revealed traumatic lesions with leukocyte infiltration, and inflammation of the intestinal wall of the infected hens after 105 days of initial infection. The possible influence of the immune and inflammatory response on the population dynamics of the parasite is discussed. PMID:19167166

  10. Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants

    PubMed Central

    van Eeden, Stephan F.

    2013-01-01

    Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants. PMID:24058272

  11. Activated systemic inflammatory response at diagnosis reduces lymph node count in colonic carcinoma

    PubMed Central

    Kennelly, Rory P; Murphy, Brenda; Larkin, John O; Mehigan, Brian J; McCormick, Paul H

    2016-01-01

    AIM To investigate a link between lymph node yield and systemic inflammatory response in colon cancer. METHODS A prospectively maintained database was interrogated. All patients undergoing curative colonic resection were included. Neutrophil lymphocyte ratio (NLR) and albumin were used as markers of SIR. In keeping with previously studies, NLR ≥ 4, albumin < 35 was used as cut off points for SIR. Statistical analysis was performed using 2 sample t-test and χ2 tests where appropriate. RESULTS Three hundred and two patients were included for analysis. One hundred and ninety-five patients had NLR < 4 and 107 had NLR ≥ 4. There was no difference in age or sex between groups. Patients with NLR of ≥ 4 had lower mean lymph node yields than patients with NLR < 4 [17.6 ± 7.1 vs 19.2 ± 7.9 (P = 0.036)]. More patients with an elevated NLR had node positive disease and an increased lymph node ratio (≥ 0.25, P = 0.044). CONCLUSION Prognosis in colon cancer is intimately linked to the patient’s immune response. Assuming standardised surgical technique and sub specialty pathology, lymph node count is reduced when systemic inflammatory response is activated. PMID:27574555

  12. Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response

    PubMed Central

    Xu, H; Sobue, T; Thompson, A; Xie, Z; Poon, K; Ricker, A; Cervantes, J; Diaz, P I; Dongari-Bagtzoglou, A

    2013-01-01

    Summary Mitis-group streptococci are ubiquitous oral commensals that can promote polybacterial biofilm virulence. Using a novel murine oral mucosal co-infection model we sought to determine for the first time whether these organisms promote the virulence of C. albicans mucosal biofilms in oropharyngeal infection and explored mechanisms of pathogenic synergy. We found that Streptococcus oralis colonization of the oral and gastrointestinal tract was augmented in the presence of C. albicans. S. oralis and C. albicans co-infection significantly augmented the frequency and size of oral thrush lesions. Importantly, S. oralis promoted deep organ dissemination of C. albicans. Whole mouse genome tongue microarray analysis showed that when compared with animals infected with one organism, the doubly infected animals had genes in the major categories of neutrophilic response/chemotaxis/inflammation significantly upregulated, indicative of an exaggerated inflammatory response. This response was dependent on TLR2 signalling since oral lesions, transcription of pro-inflammatory genes and neutrophil infiltration, were attenuated in TLR2−/− animals. Furthermore, S. oralis activated neutrophils in a TLR2-dependent manner in vitro. In summary, this study identifies a previously unrecognized pathogenic synergy between oral commensal bacteriaand C. albicans. This is the first report of the ability of mucosal commensal bacteria to modify the virulence of an opportunistic fungal pathogen. PMID:24079976

  13. Xenopus: An in vivo model for imaging the inflammatory response following injury and bacterial infection.

    PubMed

    Paredes, Roberto; Ishibashi, Shoko; Borrill, Roisin; Robert, Jacques; Amaya, Enrique

    2015-12-15

    A major goal in regenerative medicine is to identify therapies to facilitate our body׳s innate abilities to repair and regenerate following injury, disease or aging. In the past decade it has become apparent that the innate immune system is able to affect the speed and quality of the regenerative response through mechanisms that are not entirely clear. For this reason there has been a resurgent interest in investigating the role of inflammation during tissue repair and regeneration. Remarkably, there have only been a handful of such studies using organisms with high regenerative capacity. Here we perform a study of the inflammatory response following injury in Xenopus larvae, which are able to achieve scarless wound healing and to regenerate appendages, as a preamble into understanding the role that inflammation plays during tissue repair and regeneration in this organism. We characterized the morphology and migratory behavior of granulocytes and macrophages following sterile and infected wounding regimes, using various transgenic lines that labeled different types of myeloid lineages, including granulocytes and macrophages. Using this approach we found that the inflammatory response following injury and infection in Xenopus larvae is very similar to that seen in humans, suggesting that this model provides an easily tractable and medically relevant system to investigate inflammation following injury and infection in vivo. PMID:25823652

  14. Xenopus: An in vivo model for imaging the inflammatory response following injury and bacterial infection

    PubMed Central

    Paredes, Roberto; Ishibashi, Shoko; Borrill, Roisin; Robert, Jacques; Amaya, Enrique

    2015-01-01

    A major goal in regenerative medicine is to identify therapies to facilitate our body׳s innate abilities to repair and regenerate following injury, disease or aging. In the past decade it has become apparent that the innate immune system is able to affect the speed and quality of the regenerative response through mechanisms that are not entirely clear. For this reason there has been a resurgent interest in investigating the role of inflammation during tissue repair and regeneration. Remarkably, there have only been a handful of such studies using organisms with high regenerative capacity. Here we perform a study of the inflammatory response following injury in Xenopus larvae, which are able to achieve scarless wound healing and to regenerate appendages, as a preamble into understanding the role that inflammation plays during tissue repair and regeneration in this organism. We characterized the morphology and migratory behavior of granulocytes and macrophages following sterile and infected wounding regimes, using various transgenic lines that labeled different types of myeloid lineages, including granulocytes and macrophages. Using this approach we found that the inflammatory response following injury and infection in Xenopus larvae is very similar to that seen in humans, suggesting that this model provides an easily tractable and medically relevant system to investigate inflammation following injury and infection in vivo. PMID:25823652

  15. Protein synthesis in cancer patients with inflammatory response: investigations with [15N]glycine.

    PubMed

    McMillan, D C; Preston, T; Fearon, K C; Burns, H J; Slater, C; Shenkin, A

    1994-01-01

    It has been proposed that the increase in amino acid flux and derived protein synthesis rates observed in weight-losing cancer patients may contribute to an ongoing negative energy balance. The mediators and tissues responsible for such apparent increased protein synthesis have not been clearly identified. The aim of this study was to examine the relationship between protein synthetic rates in whole-body, skeletal muscle, and circulating cortisol concentrations in healthy subjects (n = 6) and cancer patients with evidence of an inflammatory response (n = 6). Protein synthetic rates were measured with a primed continuous 20-h infusion of [15N]glycine. Skeletal muscle was biopsied at laparotomy. Serum cortisol, resting energy expenditure, plasma proteins, nitrogen metabolites in urine, and skeletal muscle free amino acids were also measured. Derived whole-body and skeletal muscle protein synthetic rates in the cancer group were increased significantly (by 70 and 93%, respectively, p < 0.05). Circulating concentrations of cortisol, fibrinogen, and C-reactive protein were also significantly increased in the cancer group and indicated the presence of an inflammatory response. However, there was no significant increase in resting energy expenditure. Mechanisms by which apparent increases in whole-body and skeletal protein synthesis do not result in an increase in resting energy expenditure are discussed. We conclude that glycine utilization is increased in cancer patients but that rates of protein synthesis derived from [15N]glycine kinetics may not be valid in such patients. PMID:7919675

  16. Alcohol and inflammatory responses: summary of the 2013 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

    PubMed

    Morris, Niya L; Ippolito, Jill A; Curtis, Brenda J; Chen, Michael M; Friedman, Scott L; Hines, Ian N; Haddad, Georges E; Chang, Sulie L; Brown, Lou Ann; Waldschmidt, Thomas J; Mandrekar, Pranoti; Kovacs, Elizabeth J; Choudhry, Mashkoor A

    2015-02-01

    Loyola University Chicago, Health Sciences Campus in Maywood, Illinois hosted the 18th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting on November 22, 2013. This year's meeting emphasized alcohol's effect on inflammatory responses in diverse disease states and injury conditions. The meeting consisted of three plenary sessions demonstrating the adverse effects of alcohol, specifically, liver inflammation, adverse systemic effects, and alcohol's role in infection and immunology. Researchers also presented insight on modulation of microRNAs and stress proteins following alcohol consumption. Additionally, researchers revealed sex- and concentration-dependent differences in alcohol-mediated pathologies. PMID:25468277

  17. Nanoparticles responsive to the inflammatory microenvironment for targeted treatment of arterial restenosis.

    PubMed

    Feng, Shibin; Hu, Ying; Peng, Song; Han, Songling; Tao, Hui; Zhang, Qixiong; Xu, Xiaoqiu; Zhang, Jianxiang; Hu, Houyuan

    2016-10-01

    Coronary arterial disease (CAD) remains the leading cause of death globally. Percutaneous coronary interventions are frequently used nonsurgical techniques for treating CAD, which may unfortunately lead to arterial restenosis. Currently, there are no effective drugs that can thoroughly prevent restenosis. We hypothesize inflammation-triggerable nanomedicines may function as effective therapeutics for targeted therapy of restenosis, by preferentially releasing their payload at the diseased site. To demonstrate our hypothesis and develop targeted nanotherapies for restenosis, this study was designed to examine effectiveness of nanomedicines responsive to the inflammatory microenvironment with mild acidity and high reactive oxygen species (ROS). To this end, an acetalated β-cyclodextrin (β-CD) material (Ac-bCD) was synthesized as a pH-responsive carrier material, while a ROS-responsive material (Ox-bCD) was produced by hydrophobic functionalization of β-CD with an oxidation-labile group. Based on these two responsive materials, either pH- or ROS-responsive nanoparticles (NPs) were produced by a nanoprecipitation technique and fully characterized. Using rapamycin (RAP) as a candidate drug, responsive nanotherapies were fabricated. In vitro hydrolysis and release studies confirmed these nanovehicles and nanotherapies exhibited desirable responsive behaviors. Both in vitro cell culture and in vivo evaluations revealed their good safety profile. These responsive NPs could be effectively internalized by rat vascular smooth muscle cells, which in turn notably potentiated anti-proliferation and anti-migration activities of RAP. After intravenous (i.v.) injection, NPs may be accumulated at the injured site in the carotid artery of rats subjected to balloon angioplasty injury. Compared with a non-responsive nanotherapy based on poly(lactide-co-glycolide), treatment with either pH- or ROS-responsive nanotherapy by i.v. injection more effectively attenuated neointimal

  18. The Human Transcriptome During Nontyphoid Salmonella and HIV Coinfection Reveals Attenuated NFκB-Mediated Inflammation and Persistent Cell Cycle Disruption

    PubMed Central

    Schreiber, Fernanda; Lynn, David J.; Houston, Angela; Peters, Joanna; Mwafulirwa, Gershom; Finlay, Brett B.; Brinkman, Fiona S. L.; Hancock, Robert E. W.; Heyderman, Robert S.; Dougan, Gordon

    2011-01-01

    Background. Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses. Methods. We studied the transcriptional response in whole blood from HIV-positive patients during acute and convalescent iNTS disease compared to other invasive bacterial diseases, and to HIV-positive and -negative controls. Results. During iNTS disease, there was a remarkable lack of a coordinated inflammatory or innate immune signaling response. Few interferon γ (IFNγ)--induced genes or Toll-like receptor/transcription factor nuclear factor κB (TLR/NFκB) gene pathways were upregulated in expression. Ex vivo lipopolysacharide (LPS) or flagellin stimulation of whole blood, however, showed that convalescent iNTS subjects and controls were competent to mount prominent TLR/NFκB-associated patterns of mRNA expression. In contrast, HIV-positive patients with other invasive bacterial infections (Escherichia coli and Streptococcus pneumoniae) displayed a pronounced proinflammatory innate immune transcriptional response. There was also upregulated mRNA expression in cell cycle, DNA replication, translation and repair, and viral replication pathways during iNTS. These patterns persisted for up to 2 months into convalescence. Conclusions. Attenuation of NFκB-mediated inflammation and dysregulation of cell cycle and DNA-function gene pathway expression are key features of the interplay between iNTS and HIV. PMID:21917897

  19. From Mechanosensitivity to Inflammatory Responses: New Players in the Pathology of Glaucoma

    PubMed Central

    Križaj, David; Ryskamp, Daniel A.; Tian, Ning; Tezel, Gülgün; Mitchell, Claire H.; Slepak, Vladlen Z.; Shestopalov, Valery I.

    2013-01-01

    Purpose of the study Many blinding diseases of the inner retina are associated with degeneration and loss of retinal ganglion cells (RGCs). Recent evidence implicates several new signaling mechanisms as causal agents associated with RGC injury and remodeling of the optic nerve head. Ion channels such as Transient receptor potential vanilloid isoform 4 (TRPV4), pannexin-1 (Panx1) and P2X7 receptor are localized to RGCs and act as potential sensors and effectors of mechanical strain, ischemia and inflammatory responses. Under normal conditions, TRPV4 may function as an osmosensor and a polymodal molecular integrator of diverse mechanical and chemical stimuli, whereas P2X7R and Panx1 respond to stretch- and/or swelling-induced adenosine triphosphate release from neurons and glia. Ca2+ influx, induced by stimulation of mechanosensitive ion channels in glaucoma, is proposed to influence dendritic and axonal remodeling that may lead to RGC death while (at least initially) sparing other classes of retinal neuron. The secondary phase of the retinal glaucoma response is associated with microglial activation and an inflammatory response involving Toll-like receptors (TLRs), cluster of differentiation 3 (CD3) immune recognition molecules associated with the T-cell antigen receptor, complement molecules and cell type-specific release of neuroactive cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The retinal response to mechanical stress thus involves a diversity of signaling pathways that sense and transduce mechanical strain and orchestrate both protective and destructive secondary responses. Conclusions Mechanistic understanding of the interaction between pressure-dependent and independent pathways is only beginning to emerge. This review focuses on the molecular basis of mechanical strain transduction as a primary mechanism that can damage RGCs. The damage occurs through Ca2+-dependent cellular remodeling and is associated with parallel

  20. The efficacy of parecoxib on systemic inflammatory response associated with cardiopulmonary bypass during cardiac surgery

    PubMed Central

    Wu, Qingping; Purusram, Gunsham; Wang, Huiqing; Yuan, Ruixia; Xie, Wanli; Gui, Ping; Dong, Nianguo; Yao, Shanglong

    2013-01-01

    Aims Cardiopulmonary bypass (CPB) during cardiac surgery is well known to be associated with the development of a systemic inflammatory response. The efficacy of parecoxib in attenuating this systemic inflammatory response is still unknown. Methods Patients undergoing elective mitral valve replacement with CPB were assessed, enrolled and randomly allocated to receive parecoxib (80 mg) or placebo. Blood samples were collected in EDTA vials for measuring serum cytokine concentrations, troponin T, creatinekinase myocardial‐brain isoenzyme CK‐MB concentrations and white cell counts. Results Compared with the control group, IL‐6 and IL‐8‐values in the parecoxib group increased to a lesser extent, peaking at 2 h after the end of CPB (IL‐6 31.8 pg ml−1 ± 4.7 vs. 77.0 pg ml−1 ± 14.1, 95% CI −47.6, −42.8, P < 0.001; IL‐8 53.6 pg ml−1 ± 12.6 vs. 105.7 pg ml−1 ± 10.8, 95% CI −54.8, −49.4, P < 0.001). Peak concentrations of anti‐inflammatory cytokine IL‐10 occurred immediately after termination of CPB and were higher in the parecoxib group (115.7 pg ml−1 ± 10.5 vs. 88.4 pg ml−1 ± 12.3, 95% CI 24.7, 29.9, P < 0.001). Furthermore, the increase in neutrophil counts caused by CPB during cardiac surgery was inhibited by parecoxib. The increases in serum troponin T and CK‐MB concentrations were also significantly attenuated by parecoxib in the early post‐operative days. Peak serum concentrations of CK‐MB in both groups occurred at 24 h post‐CPB (17.4 μg l−1 ± 5.2 vs. 26.9 μg l−1 ± 6.9, 95% CI −10.9, −8.1, P < 0.001). Peak troponin T concentrations occurred at 6 h post‐bypass (2 μg l−1 ± 0.62 vs. 3.5 μg l−1 ± 0.78, 95% CI −1.7, −1.3, P < 0.001). Conclusion Intra‐operative parecoxib attenuated the systemic inflammatory response associated with CPB during cardiac surgery and lowered the biochemical markers of myocardial injury. PMID:22835079

  1. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

    PubMed Central

    Markworth, James F.; Vella, Luke; Lingard, Benjamin S.; Tull, Dedreia L.; Rupasinghe, Thusitha W.; Sinclair, Andrew J.; Maddipati, Krishna Rao

    2013-01-01

    Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0–3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a

  2. The Gamma Interferon Receptor Is Required for the Protective Pulmonary Inflammatory Response to Cryptococcus neoformans

    PubMed Central

    Chen, Gwo-Hsiao; McDonald, Roderick A.; Wells, Jason C.; Huffnagle, Gary B.; Lukacs, Nicholas W.; Toews, Galen B.

    2005-01-01

    Mice with a null deletion mutation in the gamma interferon (IFN-γ) receptor gene were used to study the role of IFN-γ responsiveness during experimental pulmonary cryptococcosis. Cryptococcus neoformans was inoculated intratracheally into mice lacking the IFN-γ receptor gene (IFN-γR−/−) and into control mice (IFN-γR+/+). The numbers of CFU in lung, spleen, and brain were determined to assess clearance; cytokines produced by lung leukocytes were measured, and survival curves were generated. In the present study, we demonstrate the following points. (i) IFN-γR−/− mice are markedly more susceptible to C. neoformans infection than IFN-γR+/+ mice. (ii) In the absence of IFN-γ signaling, pulmonary CFU continue to increase over the course of infection, and the infection disseminates to the brain. (iii) In the absence of IFN-γ receptor, recruitment of inflammatory cells in response to pulmonary cryptococcal infection is not impaired. (iv) At week 5 postinfection, IFN-γR−/− mice have recruited greater numbers of leukocytes into their lungs, with neutrophils, eosinophils, and lymphocytes accounting for this cellular increase. (v) IFN-γ signaling is required for the development of a T1 over a T2 immune response in the lung following cryptococcal infection. These results indicate that in the absence of IFN- γ responsiveness, even though the recruitment of pulmonary inflammatory cells is not impaired and the secretion of IFN-γ is not affected, IFN-γR−/− mice do not have the ability to resolve the cryptococcal infection. In conclusion, our data suggest that proper functional IFN-γ signaling, possibly through a mechanism which inhibits the potentially disease-promoting T2 response, is required for mice to confine the cryptococcal infection. PMID:15731080

  3. The Role of PPARγ in Advanced Glycation End Products-Induced Inflammatory Response in Human Chondrocytes

    PubMed Central

    Li, Yu-qing; Chen, Cheng; Cai, Wei; Zeng, Yue-lin

    2015-01-01

    Objective Advances made in the past ten years highlight the notion that peroxisome proliferator-activated receptors gamma (PPARγ) has protective properties in the pathophysiology of osteoarthritis (OA). The aim of this study was to define the roles of PPARγ in AGEs-induced inflammatory response in human chondrocytes. Methods Primary human chondrocytes were stimulated with AGEs in the presence or absence of neutralizing antibody against RAGE (anti-RAGE), MAPK specific inhibitors and PPARγ agonist pioglitazone. The expression of IL-1, MMP-13, TNF-α, PPARγ, nuclear NF-κB p65 and cytosol IκBα was determined by western blotting and real-time PCR. Results AGEs could enhance the expression of IL-1, TNF-α, and MMP-13, but the level of PPARγ was decreased in a time- and dose-dependent manner, which was inhibited by anti-RAGE, SB203580 (P38 MAPK specific inhibitor) and SP600125 (a selective inhibitor of JNK). PPARγ agonist pioglitazone could inhibit the effects of AGEs-induced inflammatory response and PPARγ down-regulation. In human chondrocytes, AGEs could induce cytosol IκBα degradation and increase the level of nuclear NF-κB p65, which was inhibited by PPARγ agonist pioglitazone. Conclusions In primary human chondrocytes, AGEs could down-regulate PPARγ expression and increase the inflammatory mediators, which could be reversed by PPARγ agonist pioglitazone. Activation of RAGE by AGEs triggers a cascade of downstream signaling, including MAPK JNK/ p38, PPARγ and NF-κB. Taken together, PPARγ could be a potential target for pharmacologic intervention in the treatment of OA. PMID:26024533

  4. Fluoxetine inhibits inflammatory response and bone loss in a rat model of ligature-induced periodontitis

    PubMed Central

    Branco-de-Almeida, Luciana S.; Franco, Gilson C. N.; Castro, Myrella L.; dos Santos, Juliana G.; Anbinder, Ana Lia; Cortelli, Sheila C.; Kajiya, Mikihito; Kawai, Toshihisa; Rosalen, Pedro L.

    2012-01-01

    Background Fluoxetine, a selective serotonin reuptake inhibitor, has recently been found to possess anti-inflammatory properties. The present study investigated the effects of fluoxetine on inflammatory tissue destruction in a rat model of ligature-induced periodontitis (PD). Methods Male Wistar rats were randomly assigned into three groups (n=10 animals/group): 1) Control rats (without ligature); 2) rats with ligature + placebo (saline; oral gavage); 3) rats with ligature + fluoxetine (20 mg/kg/day in saline; oral gavage). Histological analyses were performed on the furcation region and mesial of mandibular first molars of rats sacrificed at 15 days after ligature-induced PD. Reverse transcriptase-polymerase chain reaction (RT-PCR) and zymography were performed to analyze the mRNA expression of interleukin (IL)-1β, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase (iNOS), and the MMP-9 activity, respectively, in gingival tissues samples. Results Compared to the ligature + placebo group, alveolar bone loss was reduced in the fluoxetine group (P < 0.05), and the integrity of collagen fibers in the gingival tissue was maintained. Moreover, in gingival tissue sampled 3 days after ligature attachment, fluoxetine administration reduced IL-1β and COX-2 mRNA expression. Fluoxetine down-regulated MMP-9 activity, without affecting MMP-9 mRNA expression induced by ligature, compared to the ligature + placebo group (P < 0.05). These data suggested that fluoxetine suppressed proinflammatory responses, as well as proteolytic enzyme activity, induced by ligature. Conclusions In the present study, fluoxetine suppressed the inflammatory response and protected against periodontal bone resorption and destruction of collagen fibers, suggesting that fluoxetine can constitute a promising therapeutic approach for periodontal diseases. PMID:21966942

  5. Acute Inflammatory Responses of Nanoparticles in an Intra-Tracheal Instillation Rat Model

    PubMed Central

    Armstead, Andrea L.; Minarchick, Valerie C.; Porter, Dale W.; Nurkiewicz, Timothy R.; Li, Bingyun

    2015-01-01

    Exposure to hard metal tungsten carbide cobalt (WC-Co) “dusts” in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 μg per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs. PMID:25738830

  6. Systemic Pregabalin Attenuates Sensorimotor Responses and Medullary Glutamate Release in Inflammatory Tooth Pain Model

    PubMed Central

    Narita, Noriyuki; Kumar, Naresh; Cherkas, Pavel S.; Chiang, Chen Yu; Dostrovsky, Jonathan O.; Coderre, Terence J.; Sessle, Barry J.

    2012-01-01

    Our previous studies have demonstrated that application to the tooth pulp of the inflammatory irritant mustard oil (MO) induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0~1.2 %), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (ANOVA, p<0.05). These results suggest that pregabalin may attenuate the medullary release of glutamate and associated nociceptive sensorimotor responses in this acute inflammatory pulpal pain model, and that it may prove useful for the treatment of orofacial inflammatory pain states

  7. Cyclo-Gly-Pro, a cyclic dipeptide, attenuates nociceptive behaviour and inflammatory response in mice.

    PubMed

    Ferro, Jamylle Nunes de Souza; de Aquino, Fernanda Lima Torres; de Brito, Renan Guedes; dos Santos, Priscila Laíse; Quintans, Jullyana de Souza Siqueira; de Souza, Lucas Costa; de Araújo, Almair Ferreira; Diaz, Bruno Lourenço; Lucca-Júnior, Waldecy; Quintans-Júnior, Lucindo José; Barreto, Emiliano

    2015-12-01

    The present study aimed to investigate the antinociceptive and anti-inflammatory effects of the cyclic dipeptide cyclo-Gly-Pro (CGP) in mice. Antinociceptive activity was assessed by employing different pain models, such as formalin test, acetic acid-induced writhing, hot plate test, and carrageenan-induced hyperalgesia, in mice. The number of c-Fos-immunoreactive cells in the periaqueductal gray (PAG) was evaluated in CGP-treated mice. Anti-inflammatory activity was evaluated using paw oedema induced by carrageenan, compound 48/80, serotonin, and prostaglandin E2 (PGE2) and analyzed by plethysmometry. Quantitation of myeloperoxidase (MPO) in the paw was carried out to analyze the presence of neutrophils in the tissue. Intraperitoneal injection of CGP produced a significant inhibition in both neurogenic and inflammatory phases of formalin-induced pain. The antinociceptive effect of CGP, evaluated in the acetic acid-induced writhing test, was detected for up to 6 h after treatment. Further, in the hot plate test, antinociceptive behaviour was evoked by CGP, and this response was inhibited by naloxone. Animals treated with CGP did not present changes in motor performance. In CGP-treated mice there was an increase in the number of c-Fos-positive neurons in the periaqueductal gray. In another set of experiments, CGP attenuated the hyperalgesic response induced by carrageenan. Furthermore, CGP also reduced the carrageenan-increased MPO activity in paws. In addition, CGP also reduced the paw oedema evoked by compound 48/80, serotonin, and PGE2 . Taken together, these results may support a possible therapeutic application of the cyclic dipeptide cyclo-Gly-Pro toward alleviating nociception and damage caused by inflammation conditions. PMID:26277051

  8. Age-dependent alterations in the inflammatory response to pulmonary challenge.

    PubMed

    Linge, Helena M; Ochani, Kanta; Lin, Ke; Lee, Ji Young; Miller, Edmund J

    2015-12-01

    The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 months or greater than 18 months (approximating humans of 20 and 55-65 years), were challenged, intratracheally, with lipoteichoic acid and peptidoglycan. Cellular and cytokine evaluations were performed on both bronchoalveolar lavage fluid (BAL) and plasma, 24 h post-challenge. The plasma concentration of free thyroxine, a marker of severity in non-thyroidal illness, was also evaluated. The older animals had an increased chemotactic gradient in favor of the airspaces, which was associated with a greater accumulation of neutrophils and protein. Furthermore, macrophage migration inhibitory factor (MIF), an inflammatory mediator and putative biomarker in acute lung injury, was increased in both the plasma and BAL of the older, but not young animals. Conversely, plasma free thyroxine, a natural inhibitor of MIF, was decreased in the older animals. These findings identify age-associated inflammatory/metabolic changes following pulmonary challenge that it may be possible to manipulate to improve outcome in the older, critically ill patient. PMID:26318747

  9. Early inflammatory response in soft tissues induced by thin calcium phosphates.

    PubMed

    Rydén, L; Molnar, D; Esposito, M; Johansson, A; Suska, F; Palmquist, A; Thomsen, P

    2013-09-01

    The inflammatory response to titanium and hydroxyapatite (HA)-coated titanium in living tissue is controlled by a number of humoral factors, of which monocyte chemoattractant protein-1 (MCP-1) has been specifically linked to the recruitment of monocytes. These cells subsequently mature into tissue-bound macrophages. Macrophages adhering to the proteins adsorbed at the implant surface play a pivotal role in initiating the rejection or integration of the foreign material. Despite this, little is known about the initial inflammatory events that occur in soft tissues following the implantation of titanium and HA-coated titanium implants. In this study, circular discs of commercially pure titanium (c.p. Ti) with either a thin crystalline HA coating or amorphous HA coating or uncoated were implanted subcutaneously into rats. The implants were retrieved after 24 and 72 h. The lactate dehydrogenase (LD) activity, DNA content, expression of MCP-1, interleukin-10 (IL-10), tumor necrosis factor α (TNF-α), as well as monocyte and polymorphonuclear granulocyte counts in the exudate surrounding the implants were analyzed. There were significantly higher DNA and LD levels around the titanium implants at 24 h compared with HA-coated titanium. A rapid decrease in MCP-1 levels was observed for all the implants over the period of observation. No statistically significant differences were found between the two HA-coated implants. Our results suggest a difference in the early soft-tissue response to HA-coated implants when compared with titanium implants, expressed as a downregulation of inflammatory cell recruitment. This suggests that thin HA coatings are promising surfaces for soft tissue applications. PMID:23463679

  10. Acute inflammatory responses of nanoparticles in an intra-tracheal instillation rat model.

    PubMed

    Armstead, Andrea L; Minarchick, Valerie C; Porter, Dale W; Nurkiewicz, Timothy R; Li, Bingyun

    2015-01-01

    Exposure to hard metal tungsten carbide cobalt (WC-Co) "dusts" in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 μg per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs. PMID:25738830

  11. Systemic inflammatory response due to chloroform intoxication--an uncommon complication.

    PubMed

    Dettling, A; Stadler, K; Eisenbach, C; Skopp, G; Haffner, H T

    2016-03-01

    Well-known adverse effects of chloroform are drowsiness, nausea, and liver damage. Two cases with an uncommon complication due to chloroform intoxication are presented. In the first case, a general physician, because of nausea and dyspnea, admitted a 34-year-old woman to hospital. She developed a toxic pulmonary edema requiring mechanical ventilation for a few days, and a systemic inflammatory response syndrome (SIRS) with elevated white blood cell counts, a moderate increase of C-reactive protein, and slightly elevated procalcitonin levels. There were inflammatory altered skin areas progressing to necrosis later on. However, bacteria could be detected neither in blood culture nor in urine. Traces of chloroform were determined from a blood sample, which was taken 8 h after admission. Later, the husband confessed to the police having injected her chloroform and put a kerchief soaked with chloroform over her nose and mouth. In the second case, a 50-year-old man ingested chloroform in a suicidal attempt. He was found unconscious in his house and referred to a hospital. In the following days, he developed SIRS without growth of bacteria in multiple blood cultures. He died several days after admission due to multi-organ failure. SIRS in response to chloroform is a rare but severe complication clinically mimicking bacterial-induced sepsis. The mechanisms leading to systemic inflammation after chloroform intoxication are currently unclear. Possibly, chloroform and/or its derivates may interact with pattern recognition receptors and activate the same pro-inflammatory mediators (cytokines, interleukins, prostaglandins, leukotrienes) that cause SIRS in bacterial sepsis. PMID:25676899

  12. Systemic pregabalin attenuates sensorimotor responses and medullary glutamate release in inflammatory tooth pain model.

    PubMed

    Narita, N; Kumar, N; Cherkas, P S; Chiang, C Y; Dostrovsky, J O; Coderre, T J; Sessle, B J

    2012-08-30

    Our previous studies have demonstrated that application of inflammatory irritant mustard oil (MO) to the tooth pulp induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0-1.2%), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into