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Central Mediator (central + mediator)
Selected AbstractsNLR-containing inflammasomes: Central mediators of host defense and inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2010Katherine A. Fitzgerald First page of article [source] High glucose activates pituitary proopiomelanocortin gene expression: possible role of free radical-sensitive transcription factorsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2007Koichi Asaba Abstract Background Hyperglycemia is recognized as a metabolic stress, and indeed it is known to stimulate hypothalamo-pituitary-adrenal (HPA) axis, a representative anti-stress system, in patients with diabetes mellitus or in animal models of hyperglycemia. Thus, we tried to clarify the molecular mechanism of glucose-induced HPA axis activation. Methods We studied the effect of high glucose on the transcriptional regulation of proopiomelanocortin (POMC) gene that encodes adrenocorticotropic hormone, a central mediator of HPA axis, using AtT20 corticotroph cell line in vitro. Results We found that high glucose concentration (24 mM) significantly stimulated the 5,-promoter activity of POMC gene. The effect was promoter-specific, and was mimicked by nuclear factor-kappaB (NF-,B)- or AP1-responsive promoters but not by cAMP-responsive element or serum-response element-containing promoters. Furthermore, the stimulatory effect of high glucose on POMC gene was eliminated by NF-,B and AP1 inhibitors, suggesting the involvement of the transcriptional factors. The POMC 5,-promoter has the canonical NF-,B consensus sequence, and gel shift assay showed the binding of NF-,B to the element. Finally, the effect of high glucose was completely abolished by treatment with a radical quencher 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). Conclusions Our data suggest that hyperglycemia activates POMC gene expression, at least partly, via NF-,B/AP1, and that high-glucose-induced free radical generation may mediate the activation of these transcription factors, which in turn stimulates the transcription of POMC gene. Copyright © 2006 John Wiley & Sons, Ltd. [source] The story of O , is oxytocin the mediator of the placebo response?NEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2009P. Enck Abstract, While the placebo responses in various medical conditions have been shown to follow a few basic principles such as expectancies, reward learning and Pavlovian conditioning, the underlying neurobiology and the mediating hormonal and/or neuromodulating processing have remained obscure. We here report the collected evidence that oxytocin (OXT), a 389-amino acid polypeptide located on chromosome 3p25 that is released in the brain (hypothalamus) and in peripheral tissue, is the central mediator of the placebo response: we hypothesize that exogenous OXT via an OXT agonist will enhance the placebo response, while exogenous OXT blockade by an antagonist will reduce the placebo response in placebo analgesia and other placebo models. It is furthermore proposed that the placebo response in trials may be predicted by circulating plasma OXT levels, the OXT receptor density in the brain and/or the presence of one or more of the single nucleotide polymorphisms of the OXT promoter gene. [source] Discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes,THE JOURNAL OF PATHOLOGY, Issue 2 2009Andreas R Klatt Abstract We deciphered constituent parts of a signal transduction cascade that is initiated by collagen II and results in the release of various pro-inflammatory cytokines, including interleukin-6 (IL-6), in primary human chondrocytes. This cascade represents a feed-forward mechanism whereby cartilage matrix degradation is exacerbated by the mutually inducing effect of released collagen II fragments and pro-inflammatory cytokines. We previously proposed discoidin domain receptor 2 as a central mediator in this event. Since this cascade plays a prominent role in the pathogenesis of osteoarthritis, our study further investigates the hypothesis that discoidin domain receptor 2 is a candidate receptor for collagen II, and that transcription factor NF,B, lipid kinase PI3K, and the MAP kinases are constituent parts of this very signal transduction cascade. To accomplish this, we selectively knocked down the molecules of interest in primary human chondrocytes, induced the specified cascade by incubating primary human chondrocytes with collagen II, and observed the outcome, specifically the changes in interleukin-6 release. Knockdown was performed by siRNA-mediated gene silencing in the case of discoidin domain receptor 2 (DDR2) or by using specific inhibitors for the remainder of the molecules. Results indicated that discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes and that MAP kinases p38, JNK and ERK, as well as transcription factor NF,B, are integral components of intracellular collagen II signalling. Given the detrimental role of these molecules in osteoarthritis, our findings provide new targets for more specific therapeutics, which may have fewer side effects than those currently applied. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis,ARTHRITIS & RHEUMATISM, Issue 8 2010David C. Wilson Objective To examine both the source of follistatin-like protein 1 (FSTL-1) and the factors that induce its expression in arthritis, and to determine whether juvenile rheumatoid arthritis (JRA) is characterized by overexpression of FSTL-1. Methods FSTL-1 expression patterns were analyzed by immunohistochemical staining of joint tissue derived from mice with collagen-induced arthritis. Induction of FSTL-1 secretion was assessed in osteoblasts, adipocytes, and human fibroblast-like synoviocytes in response to transforming growth factor , (TGF,), interleukin-1, (IL-1,), tumor necrosis factor , (TNF,), and IL-6. In addition, sera and synovial fluid from children with oligoarticular, polyarticular, or systemic-onset JRA were assayed for FSTL-1 using a custom enzyme-linked immunosorbent assay. FSTL-1 concentrations in these patients were assessed for correlations with the erythrocyte sedimentation rate (ESR) and platelet count. Results Immunohistochemical staining of murine joint sections demonstrated expression of FSTL-1 in all cell types of the mesenchymal lineage, including osteocytes, chondrocytes, adipocytes, and fibroblasts. FSTL-1 could be induced in osteoblasts, adipocytes, and human fibroblast-like synoviocytes by TGF,, IL-1,, TNF,, and IL-6. The IL-1, response was significantly greater than the TNF, response (P < 0.05). In human serum and synovial fluid, only those samples from children with the systemic-onset JRA subtype had elevated concentrations of FSTL-1. The synovial fluid concentrations of FSTL-1 were 2,3-fold higher than the serum concentrations. The elevation in serum FSTL-1 concentrations seen in children with systemic-onset JRA correlated closely with elevations in the ESR and platelet count. Conclusion These findings demonstrate that the arthritic joint matrix is a major source of FSTL-1 and that IL-1, is a central mediator of FSTL-1 secretion. Furthermore, FSTL-1 may represent a useful biomarker of disease activity in systemic-onset JRA. [source] Lipids as central mediators of cellular signallingIUBMB LIFE, Issue 8 2006Stuart M. Pitson No abstract is available for this article. [source] Melatonin reduces dimethylnitrosamine-induced liver fibrosis in ratsJOURNAL OF PINEAL RESEARCH, Issue 2 2004Veysel Tahan Abstract:, Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)-induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice. [source] Xanthohumol, a chalcon derived from hops, inhibits hepatic inflammation and fibrosisMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue S2 2010Christoph Dorn Abstract Xanthohumol (XN) is a major prenylated chalcone found in hops, which is used to add bitterness and flavor to beer. In this study, we first investigated the effects of XN on hepatocytes and hepatic stellate cells (HSC), the central mediators of liver fibrogenesis. XN inhibited the activation of primary human HSC and induced apoptosis in activated HSC in vitro in a dose dependent manner (0,20,,M). In contrast, XN doses as high as 50,,M did not impair viability of primary human hepatocytes. However, in both cell types XN inhibited activation of the transcription factor NF,B and expression of NF,B dependent proinflammatory genes. In vivo, feeding of XN reduced hepatic inflammation and expression of profibrogenic genes in a murine model of non-alcoholic steatohepatitis. These data indicate that XN has the potential as functional nutrient for the prevention or treatment of non-alcoholic steatohepatitis or other chronic liver disease. [source] | |||||||||||||