Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although its impact on the acute phase response is clear, little is known regarding the regulation of interleukin-6 (hepatocyte-stimulating factor) production. We evaluated its relationship with the potent immunosuppressive eicosanoid PGE2 in endotoxin (LPS)-stimulated Kupffer cells (KC). KC were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 X 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml LPS. Supernatant IL-6 levels (ng/ml) were measured with the B9.9 hybridoma proliferative bioassay, and PGE2 levels (ng/ml) by radioimmunoassay. Negligible supernatant IL-6 and PGE2 were measured at all culture intervals in unstimulated KC or those cultured with the LPS-inhibitor polymyxin-B (10 micrograms/ml). With LPS, KC IL-6 production increased in parallel with PGE2 for 24 hr before decreasing as PGE2 continued to rise. When indomethacin treatment blocked KC PGE2 production, IL-6 levels significantly increased. We conclude that PGE2 produced by activated Kupffer cells appears to down-regulate IL-6 secretion. Autocrine effects by PGE2 may locally regulate the hepatic acute phase response by limiting the KC-derived IL-6 available to act on neighboring hepatocytes.
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PMID:Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2. 236 12

Tumour necrosis factor-alpha (TNF-alpha) is secreted by macrophages in response to inflammation, infection and cancer. Sublethal doses of recombinant TNF-alpha to rats causes cachexia, anaemia and inflammation. TNF-alpha plays a major part in tissue inflammation and remodelling by stimulating production of collagenase. Cellular responses to TNF-alpha are initiated by binding to high-affinity cell surface receptors. TNF-alpha then profoundly affects gene regulation, stimulating the fos, myc, interleukin-1 and interleukin-6 genes and inhibiting the type I collagen gene. Here we demonstrate that TNF-alpha also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-alpha stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription. This may be a key mechanism for mediating at least some of the biological effects of TNF-alpha.
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PMID:Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. 253 68

This review considers the mechanisms controlling collagen deposition in mammalian lung in five different states: normal development, fibrosis, erosion, pneumonectomy, and the steady state. Deposition is the net result of positive and negative processes. The major positive processes are control of cell number and type, regulation of transcription and translation, post-translational modifications, fibril formation, and covalent cross-linking. The negative mechanisms are intracellular degradation, collagenase-mediated degradation, and phagocytosis, and they are integral to the life cycle of collagen. Cytokines and growth factors have many and complex effects on all the processes that constitute collagen metabolism. Interleukin-1 and tumor necrosis factor-alpha can either stimulate or inhibit collagen accumulation, presumably depending on the immediate environment. Interleukin-6 inhibits collagen degradation, and gamma-interferon inhibits collagen production. Platelet derived growth factor and fibroblast growth factor have powerful mitogenic effects on connective tissue cells in lung, and can also affect collagen production directly. Transforming growth factor-beta activates a battery of processes that uniformly contribute to accumulation of collagen. Transforming growth factor-beta may be the "master switch" for a fibrotic program in lung. Therapeutic approaches to controlling lung fibrosis by manipulating cytokine levels are promising. Prostaglandin E has uniformly negative effects on net collagen accumulation and may play a central role in an erosion program.
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PMID:Control of collagen deposition in mammalian lung. 777 Apr 62

Rats were treated with alcohol either acutely (continuous, 7-hr intravenous infusion; blood alcohol levels approximately 35 mM) or chronically (liquid diet, 12-14 weeks). Three hr before killing, the animals received Gram-negative bacterial lipopolysaccharide (LPS) or saline. Hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells were isolated by liver collagenase perfusion and centrifugal elutriation, and used for measurements of recombinant human [125I]interleukin-6 binding. Dissociation constant (Kd) and the amount of cell-surface receptors (Bmax) were measured on whole cells, at 4 degrees C. Two binding sites were detected on all three cell types: high-affinity (Kd1, from 20 to 125 pM) and low-affinity (Kd2, from 0.2 to 2 nM), with low Bmax (Bmax, from 0.4 to 12 fmol/10(6) cells) and high Bmax (Bmax2, from 10 to 210 fmol/10(6) cells). Hepatocytes displayed an 8-fold higher binding capacity for high-affinity sites (Bmax1) than the other two cell types. Acute ethanol treatment induced the following significant changes in the binding parameters: a decrease in Kd1 for hepatocytes and Kupffer cells, an increase in Bmax2 for hepatocytes, and a decrease in Bmax1 for Kupffer cells. Although the control (nonalcoholic) liquid diet per se completely suppressed the high-affinity binding sites, alcohol-containing diet induced only one change: a significant increase in Kd2 for hepatocytes. No changes in the binding parameters were seen after LPS administration to the chronically treated group. In the acute group, LPS mimicked alcohol action on hepatocyte binding parameters. Alcohol blunted LPS effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of acute and chronic alcohol administration to rats on the expression of interleukin-6 cell-surface receptors of hepatic parenchymal and nonparenchymal cells. 784 8

In the present study, we demonstrate that both interleukin-1 (IL-1) and interleukin-6 (IL-6) induced a significant decrease in glycosaminoglycan (GAG) synthesis and, more strikingly, secretion by 7 and 13 day-old chick embryo skin fibroblasts. We demonstrated that interleukin treatment also inhibited the synthesis of collagenase-digestible proteins (type I collagen). In addition, tissue culture supernatants (conditioned media, CM) were tested for reactivity for IL specific ELISAs and for their ability to stimulate proliferative responses in mouse thymocytes and hybridoma cells. Our findings demonstrate that chick embryo skin fibroblasts spontaneously produce IL-1 and, in even greater amounts, IL-6. Highest levels of interleukin secretion were found in the CM of 13 day-old fibroblasts and the IL-1 beta isoform was predominant over IL-1 alpha. Pretreatment of the fibroblasts with either IL-1 or IL-6 increased the secretion of both cytokines. Increased IL-1 levels were correlated with enhanced IL-1 bioactivity in the CM of IL-6 treated fibroblasts. By contrast, the raised concentrations of IL-1 in the CM of IL-1 treated cells and IL-6 in the CM of IL-1 or IL-6 treated fibroblasts failed to translate into augmented bioactivity. These observations, taken together, indicated that IL-1 and IL-6 are able to regulate the synthesis and secretion of ECM macromolecules of developing connective tissues and the cytokine release by chick embryo skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 and interleukin-6 differentially regulate the accumulation of newly synthesized extracellular matrix components and the cytokine release by developing chick embryo skin fibroblasts. 784 37

Previous work has shown that fibroblast-derived collagenase/matrix-metalloproteinase-1 (MMP-1), responsible for the breakdown of dermal interstitial collagen, was dose-dependently induced in vitro and in vivo by UVA irradiation and this induction was at least partly mediated by interleukin-6 (IL-6). We here provide evidence that UVA-induced IL-1 alpha and IL-1 beta play a central role in the induction of the synthesis both of IL-6 and collagenase/MMP-1. In contrast to the late increase of IL-1 alpha and IL-1 beta mRNA levels at 6 h postirradiation, bioactivity of IL-1 is already detectable at 1 h postirradiation. This early peak of IL-1 bioactivity appears to be responsible for the induction of IL-6 synthesis and together with IL-6 lead to an increase of the steady-state mRNA level of collagenase/MMP-1 as deduced from studies using IL-1 alpha and IL-1 beta antisense oligonucleotides or neutralizing antibodies against IL-1 alpha and IL-1 beta. Besides the early posttranslationally controlled release of intracellular IL-1, a latter pretranslationally controlled synthesis and release of IL-1 perpetuates the UV response. From these data we suggest a UV-induced cytokine network consisting of IL-1 alpha, IL-1 beta and IL-6, which via interrelated autocrine loops induce collagenase/MMP-1 and thus may contribute to the loss of interstitial collagen in cutaneous photoaging.
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PMID:UVA-induced autocrine stimulation of fibroblast-derived collagenase/MMP-1 by interrelated loops of interleukin-1 and interleukin-6. 804 11

Biochemical, histologic, and immunohistochemical analyses were performed on 34 interface membranes obtained from 33 patients during revision total knee arthroplasty. The membranes had surrounded components of cementless (n = 11) and cemented (n = 23) knee prostheses that were aseptically loose. None of these implant failures was caused by catastrophic polyethylene erosion leading to metal-to-metal contact. The histologic findings were similar in the membranes from cemented and cementless knee components: small polyethylene debris within macrophages and large birefringent polyethylene debris within foreign-body giant cells. Metallic debris was seen in membranes from both groups, but cemented membranes had more polymethylmethacrylate particles and more hyalinization. Intracytoplasmic asteroid bodies were observed in several foreign-body giant cells in both types of membranes. No significant differences were found between the two groups in levels of collagenase, prostaglandin E2 (PGE2), interleukin-1 (IL-1), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha), nor in the population of inflammatory cells stained with IL-1, IL-6, and TNF-alpha antibodies. Membranes that had surrounded components with radiographic evidence of diffuse or localized periprosthetic bone loss released significantly more collagenase, IL-1, IL-6, and TNF than did membranes from components without bone loss. These two groups, however, did not have significantly different PGE2 levels. These findings suggest that polyethylene and metal debris may play a role in macrophage activation and the release of mediators of bone resorption in the membranes surrounding failed cemented and cementless total knee implants.
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PMID:A biochemical, histologic, and immunohistologic analysis of membranes obtained from failed cemented and cementless total knee arthroplasty. 799 73

Treatment of rats with bacterially derived lipopolysaccharide (LPS), a condition that mimics acute endotoxemia, results in a significant increase in the number of endothelial cells and macrophages in the liver. This is correlated with the release of proinflammatory and cytotoxic mediators that induce liver damage. In the present studies, we analyzed the effects of various inflammatory mediators released during the pathogenesis of hepatic injury on proliferation of liver nonparenchymal cells. To induce acute endotoxemia female Sprague-Dawley rats were injected intravenously with 5 mg/kg LPS. Endothelial cells and macrophages were isolated 48 h later by combined collagenase and pronase perfusion of the liver followed by centrifugal elutriation. Interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) had no effect on proliferation of either endothelial cells or macrophages. In contrast, whereas interleukin-1 beta (IL-1 beta) inhibited the proliferation of endothelial cells from untreated rats, this cytokine stimulated the growth of cells from endotoxemic rats. The colony-stimulating factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), also markedly enhanced the proliferation of endothelial cells, as well as macrophages from endotoxemic rats. Macrophages from endotoxemic rats were more sensitive to the colony-stimulating factors than cells from untreated rats. In contrast, the inflammatory mediators LPS and interferon-gamma (IFN-gamma) inhibited endothelial cell and macrophage growth, an effect that was partially blocked in endothelial cells by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). This suggests that growth inhibition in these cells is mediated, in part, by nitric oxide. Interestingly, in both endothelial cells and macrophages from endotoxemic rats, GM-CSF, M-CSF, and IL-1 beta synergized with LPS and IFN-gamma to induce nitric oxide production. This was correlated with a further inhibition of proliferation that was partially reversed by L-NMMA in endothelial cells but not macrophages. Taken together these data demonstrate that endothelial cell and macrophage proliferation in the liver is controlled by a variety of mediators released during endotoxemia; however, the mechanisms regulating growth in the two cell types are distinct.
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PMID:Regulation of hepatic endothelial cell and macrophage proliferation and nitric oxide production by GM-CSF, M-CSF, and IL-1 beta following acute endotoxemia. 814 21

The islet from human fetal pancreas was separated by collagenase type V (0.5 mg/ml) and cultured to observe spontaneous secretion of interleukin-6 (IL-6), its relationship to insulin secretion, regulatory effect of IL-6 on insulin secretion of islets and IL-6 gene expression of human fetal islets. IL-6 was secreted by cultured human fetal islets in vitro and paralleled to their insulin secretion. The MH60.BSF2 cell proliferated by 50 folds when cultured to the supernatant of human fetal islets. RNA dot hybridization with bioting-labelled IL-6 cDNA showed that IL-6 gene expressed on human fetal islets. IL-6 promoted the insulin secretion of islets dose-dependently. The results suggested that IL-6 may be one of the promoting or regulating factors in the insulin secretion of islets.
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PMID:[Interleukin-6 gene expression of human fetal islets and its relation to insulin secretion]. 831 93

Interleukin-1 (IL-1) and interleukin-6 (IL-6) derived from Kupffer cells are major inducers of hepatic inflammation and the acute phase response. The present studies demonstrate that liver endothelial cells also produce significant quantities of IL-1 and IL-6, suggesting that these cells also participate in these processes. Endothelial cells and macrophages were isolated from female Sprague-Dawley rats by combined collagenase and pronase perfusion of the liver followed by centrifugal elutriation. In the absence of stimulation, endothelial cells were found to spontaneously produce IL-1 and IL-6 in a time-dependent manner, reaching maximal levels after 10 h in culture for IL-1 and 6-8 h for IL-6. The amount and kinetics of cytokine production by hepatic endothelial cells were similar to those observed with Kupffer cells. In further studies, the effects of lipopolysaccharide (LPS), a potent liver macrophage activator and inflammatory agent, on cytokine release were analyzed. Treatment of rats with LPS resulted in a decrease in IL-1 release by both cell types compared to cells from untreated animals. In contrast, LPS treatment had no major effect on IL-6 release. We also found that both macrophages and endothelial cells could be induced to produce additional IL-1 and IL-6 by treatment with LPS in vitro, but only if they were preincubated for at least 24 h prior to stimulation with LPS and analyzed for cytokine release. These data demonstrate that liver endothelial cells, like Kupffer cells, have the capacity to produce immunoregulatory and proinflammatory cytokines.
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PMID:Characterization of interleukin-1 and interleukin-6 production by hepatic endothelial cells and macrophages. 844 25


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