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)

The steady-state levels of extracellular matrix proteins are regulated by the rates of their synthesis and degradation. Metalloproteinases and their specific inhibitors, tissue inhibitor of metalloproteinases-1 and -2 are believed to play a crucial role in extracellular matrix protein degradation. Here we show that the tissue inhibitor of metalloproteinases-1 is expressed in rat hepatocytes in primary culture and regulated by inflammatory cytokines. Rat hepatocytes constitutively express mRNA of tissue inhibitors of metalloproteinases-1 at a low level. Incubation with conditioned medium from lipopolysaccharide-stimulated human monocytes led to a dramatic induction of mRNA of tissue inhibitors of metalloproteinases-1. The inflammatory cytokines interleukin-1 beta, interleukin-6, interleukin-11, leukemia inhibitory factor and ciliary neurotrophic factor were also capable of stimulating expression of mRNA of tissue inhibitors of metalloproteinases-1. Among these cytokines interleukin-6 was the most potent stimulator. The combination of interleukin-1 beta, interleukin-6 and interleukin-11 synergistically up-regulated mRNA of tissue inhibitors of metalloproteinases-1. The synthetic glucocorticoid dexamethasone dose dependently inhibited constitutive and interleukin-6-induced expression of tissue inhibitors of metalloproteinases-1. A possible involvement of tissue inhibitor of metalloproteinases-1 in the pathogenesis of liver fibrosis and cirrhosis is discussed.
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PMID:Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures. 824 70

Ito cells, vitamin A-storing perisinusoidal cells, are believed to undergo myofibroblastic transformation in liver fibrogenesis. Our previous studies have shown that a diet high in polyunsaturated fat was key for induction of experimental alcoholic liver fibrosis. To investigate the cellular basis for this fibrogenic effect of a high-fat diet, we analyzed the content of vitamin A and cellular retinol binding protein (CRBP), the steady-state mRNA levels of procollagen-alpha1(I), transforming growth factor-beta1 (TGF-beta1), interleukin-6 (IL-6), and smooth muscle alpha-actin (alpha-SM) in freshly isolated Ito cells from rats given isocaloric amounts of ethanol and a low- or high-fat diet. After 10 wk, the Ito cell content of retinyl palmitate was severely reduced in both the high- and low-fat diet-ethanol-fed animals to 13-17% of those measured in respective pair-fed controls. On the other hand, the content of CRBP was reduced in the high-fat-ethanol rats but not in the low-fat-ethanol group. The cells from the high-fat-ethanol but not low-fat ethanol rats showed an 18-fold increase in procollagen-alpha1(I) mRNA at 17 wk, which was accompanied by 2.8- and 2.3-fold enhancement of TGF-beta1 and alpha-SM transcripts. IL-6 mRNA was not detected in the cells from any groups. These results demonstrate 1) myofibroblastic activation of Ito cells is evident in rats given a high-fat diet and ethanol but not in the low-fat-ethanol animals; 2) vitamin A depletion of Ito cells is the early and general effect of chronic ethanol intake but does not necessarily predict subsequent myofibroblastic activation; 3) reduced CRBP level is more closely associated with the subsequent cellular activation seen under the high-fat-ethanol regimen; and 4) IL-6 is not expressed in vivo by Ito cells from either normal livers or livers with alcoholic liver fibrosis.
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PMID:Effects of dietary polyunsaturated fat on ethanol-induced Ito cell activation. 892 87

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in numerous diseases but the correlation between liver fibrosis and IL-6 role is not clear. We studied IL-6 levels in 50 HCVAb+ patients with liver cirrhosis (grouped into A, B and C, Child classes) and in 27 healthy control subjects. IL-6 serum levels were significantly increased in the former (p < 0.005) suggesting that IL-6 stimulates and sustains liver fibrosis. In cirrhotic subjects, the rise in IL-6 serum levels is due to impaired hepatic clearance of this cytokine, while its production remains steady.
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PMID:Interleukin-6 in hepatitis C cirrhosis. 906 27

Patients with alcoholic hepatitis have several manifestations of the acute phase response (APR) and have elevated blood levels of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. We have previously shown that liver stellate cells express interleukin-6 mRNA and protein and respond to this cytokine with increased expression of alpha1(I) procollagen mRNA. We further showed that the production of an APR episode stimulates a transient expression of alpha1(I) procollagen mRNA in the liver. In this communication we demonstrate that the concomitant induction of a weekly APR episode in rats with a schedule of CCl4 to produce cirrhosis, accelerates the development of liver fibrosis. We show that the enhancement of liver fibrosis is due, in part, to further upregulation in the expression of alpha1(I) procollagen and tissue inhibitor of metalloproteinases-1 mRNAs above values observed in control rats receiving only CCl4. The effect of the APR appears to have specificity since not all the mRNAs measured were equally affected. Altogether, these results suggest that increased blood or liver levels of APR cytokines, whether induced by APR episodes, endotoxin or other unrelated causes, may contribute to the development of liver fibrosis by enhancing the expression of type I collagen and of tissue inhibitor of metalloproteinases-1 mRNAs.
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PMID:Accelerated development of liver fibrosis in CCl4-treated rats by the weekly induction of acute phase response episodes: upregulation of alpha1(I) procollagen and tissue inhibitor of metalloproteinase-1 mRNAs. 930 Jul 99

Chronic intermittent injection of carbon tetrachloride (CCl4) for more than 10 weeks induced liver fibrosis in mice, as evidenced by positive Azan staining and increased intrahepatic collagen content. Preceding the onset of liver fibrosis, interleukin-6 (IL-6) gene expression was enhanced in liver and immunoreactive IL-6 was detected in infiltrating inflammatory cells. To delineate the role of IL-6 in this process, we treated IL-6-deficient mice with CCl4 in a similar manner for 12 weeks, after which fibrotic changes were less evident and serum albumin levels were lower in IL-6-deficient than wild-type mice. Moreover, CCl4-induced expression of transforming growth factor beta1 and hepatocyte growth factor genes in liver was significantly reduced in IL-6-deficient mice. Thus, IL-6 may be vitally involved in fibrotic changes and maintenance of serum albumin levels, partly by modulating intrahepatic expression of these cytokines.
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PMID:Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice. 1053 16

The C5a-anaphylatoxin which is generated by limited proteolysis upon activation of the fifth component of complement may be induced by the classical, the alternative or the lectin pathway. C5a has been shown, under normal conditions, to induce the release of prostanoids from Kupffer cells (KC) and hepatic stellate cells (HSC) and thereby indirectly to increase glucose output from hepatocytes (HC). A direct action of C5a on HC would require the expression of the specific C5a receptor (C5aR). In studies using quantitative RT-PCR it was shown that non-stimulated HC lack C5aR, in contrast to KC, HSC and sinusoidal endothelial cells (SEC) all of which contained mRNA for the C5aR in decreasing amounts. FACS analyses, immunohisto- and immunocytochemistry as well as functional analyses confirmed the results of the RT-PCR assays. Under inflammatory situations the C5aR was found to be upregulated in various organs and tissues which included the liver. Interleukin-6 (IL-6) as a main inflammatory mediator in the liver induced a de novo expression of functional C5aR in HC in-vitro and in-vivo. In contrast, LPS failed to induce C5aR directly in cultured HC in-vitro but induced C5aR in HC in vivo and in co-cultures of HC and KC which release IL-6 upon stimulation with LPS. So far, the only known effector function of C5a on HSC was the induction of prostanoid release. In an approach to reveal new functions of C5aR in HSC, the cells responsible for liver fibrosis, it could be shown that C5a upregulated fibronectin-specific mRNA five-fold whereas entactin, collagen IV and the structure protein smooth muscle actin were not affected. In addition, C5a did not upregulate specific mRNA for the profibrotic cytokine TGF-beta1 in either isolated KC or HSC. Thus, C5a alone appears to have only a limited role in the induction of liver fibrosis.
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PMID:Expression and induction of anaphylatoxin C5a receptors in the rat liver. 1250 7

Chronic liver injury causes liver regeneration, resulting in fibrosis. The proinflammatory cytokine tumor necrosis factor (TNF) is involved in the pathogenesis of many acute and chronic liver diseases. TNF has pleiotropic functions, but its role in liver fibrosis has not been clarified. Chronic repeated injection of CCl4 induces liver fibrosis in mice. We examined whether signaling through TNF receptors was critical for this process, using mice lacking either TNF receptor (TNFR) type 1 or TNFR type 2 to define the pathophysiologic role of TNFR signals in liver fibrosis. Liver fibrosis caused by chronic CCl4 exposure was TNF-dependent; histological fibrosis was seen in wild-type (WT) and TNFR-2 knockout (KO) mice, but not in TNFR-1 KO mice. Furthermore, a marked reduction in procollagen and TGF-beta synthesis was observed in TNFR-1 KO mice, which also had little detectable NF-kappa B, STAT3, and AP1 binding, and reduced levels of liver interleukin-6 (IL-6) mRNA compared to WT and TNFR-2 KO mice. In conclusion, our results indicate the possibility that NF-kappa B, STAT3, and AP1 binding by signals transduced through TNFR-1 plays an important role in liver fibrosis formation.
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PMID:Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice. 1576 Jun 80

Interleukin-6 (IL-6) is an important cytokine in liver regeneration, and elevated levels of IL-6 have been demonstrated in patients with chronic liver diseases (CLD). Many biological effects of IL-6 depend on naturally occurring soluble IL-6 receptors. In the present study we measured the concentrations of IL-6 and its soluble receptors in the sera of patients with CLD related to hepatitis C virus (HCV) infection. We studied 77 patients with varying degrees of HCV-related CLD. Serum levels of IL-6 and its soluble receptors (sIL-6R, sgp130) were measured by enzyme-linked immunosorbent assay. Serum IL-6 and sIL-6R were elevated in patients with CLD compared with healthy subjects. Serum levels of sgp130 did not differ between patients with chronic hepatitis and healthy subjects. However, in patients with liver cirrhosis, sgp130 was significantly elevated and was positively correlated with total bilirubin and negatively correlated with cholinesterase and prothrombin time. Our study demonstrated that in patients with HCV-related CLD, serum IL-6 and its soluble receptor levels are correlated with both liver function impairment and the degree of liver fibrosis. These observations suggest that the balance of IL-6 and its soluble receptors may correspond to the state of liver damage in patients with CLD.
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PMID:Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection. 1669 22

The liver is a unique organ with respect to its anatomical location, allowing continuous blood flow from the gastrointestinal tract through the sinusoids, and its cellular composition, comprising metabolically active hepatocytes, nonhepatocytic parenchymal cells, and various immune cell populations. Cytokines are key mediators within the complex interplay of intrahepatic immune cells and hepatocytes, as they can activate effector functions of immune cells, as well as hepatocytic intracellular signaling pathways controlling cellular homeostasis. Kupffer cells and liver-infiltrating monocyte-derived macrophages are primary sources of cytokines such as tumor-necrosis factor-alpha (TNF-alpha) and interleukin-6. The liver is also enriched in natural killer (NK) and NK T cells, which fulfill functions in pathogen defense, T cell recruitment, and modulation of liver injury. TNF-alpha can activate specific intracellular pathways in hepatocytes that influence cell fate in different manners, e.g., proapoptotic signals via the caspase cascade, but also survival pathways, namely the nuclear factor (NF)-kappaB pathway. NF-kappaB regulates important functions in liver physiology and pathology. Recent experiments with genetically modified mice demonstrated important and partly controversial functions of this pathway, e.g., in cytokine-mediated hepatocyte apoptosis or ischemia-reperfusion injury. The exact dissection of the contribution of recruited and resident immune cells, their soluble cytokine and chemokine mediators, and the intracellular hepatocytic response in liver homeostasis and injury could potentially identify novel targets for the treatment of acute and chronic liver disease, liver fibrosis, or cirrhosis.
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PMID:Inflammatory pathways in liver homeostasis and liver injury. 1860 Apr 81

The aim of this study was to investigate the relationship between anti-fibrotic effect of Panax notoginseng saponins (PNS) and serum cytokines in rat hepatic fibrosis. Hepatic fibrosis induced by carbon tetrachloride (CCl(4)) was studied in animal models using SD rats. Liver index, serum alanine amino transferase (ALT), aspartate amino transferase (AST), transforming growth factor-beta1 (TGF-beta1), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured, respectively. Liver index and the degree of liver fibrosis were also determined. Our results showed that the levels of ALT, AST and liver index in PNS-treated group were markedly lower than those in model group. PNS therapy also significantly attenuated the degree of hepatic fibrosis, collagen area and collagen area percent in liver tissue. Furthermore, the levels of serum TGF-beta1, TNF-alpha and IL-6 were strikingly reduced in PNS-treated group compared with model group while the production of IL-10 was up-regulated. These findings demonstrate that PNS has certain therapeutic effects on hepatic fibrosis probably by immunoregulating the imbalance between pro-fibrotic and anti-fibrotic cytokines.
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PMID:Relationship between anti-fibrotic effect of Panax notoginseng saponins and serum cytokines in rat hepatic fibrosis. 1963 2


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