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)

Human malignant non-Hodgkin's lymphomas (NHL) represent a heterogeneous group of neoplasms, which vary in their clinical behavior and pathophysiology. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been shown to play a role in the pathophysiology and clinical aggressiveness of human NHL. In this setting, MMP-9 and TIMP-1 appear to be the most important members of the MMP and TIMP families, and overexpression of both correlates with a poor clinical outcome of patients with NHL. MMP-9 and TIMP-1, however, act through different mechanisms and are produced by different cell types. Expression of both is upregulated by interleukin-6 (IL-6), a cytokine that is known as one of the factors involved in the pathophysiology of human NHL. In this review we summarize the complex regulation of MMP and TIMP expression in human NHL and propose a mechanism by which MMP-9, TIMP-1 and IL-6 may influence the biology of these tumors.
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PMID:Matrix metalloproteinases and their tissue inhibitors - expression, role and regulation in human malignant non-Hodgkin's lymphomas. 1134 32

Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.
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PMID:Dietary fatty acids and immune reactions in synovial tissue. 1291 34

In this study, we investigated the effect of inflammatory cytokines on matrix metalloproteinase (MMP-1) and TIMP-1 production in human dermal fibroblasts, which play a pivotal role in wound healing, ranging from the synthesis and remodeling of extracellular matrix (ECM) to the synthesis of growth factors. The balance of MMPs and TIMPs is crucial in directing successful wound repair. Human adult dermal fibroblasts were seeded in six well plates (7.5 x 10(4) cells/ml) in complete media. Eighty to ninety percent confluent cells were treated with interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml) for 6h in serum free media with suitable controls run in triplicate. Supernatants were assayed for pro-MMP-1 & TIMP-1. Extracted total RNA was used for reverse transcription polymerase chain reaction (RT-PCR) with sequence specific primers for MMP-1, TIMP-1 and beta-actin. Signal intensity was normalized to the internal control (beta-actin). Statistical analysis used ANOVA. MMP-1 and TIMP-1 mRNA expression were markedly increased with IL-6 and TNF-alpha treatment and remains unchanged with IL-1beta. Pro-MMP-1 protein levels are unchanged with TNF-alpha and significantly increased with IL-1beta and IL-6 treatment. However, TNF-alpha significantly increases TIMP-1 protein levels. Data suggests differential regulation of MMP-1 and TIMP-1 protein levels by the cytokines found in stimulated dermal fibroblasts. Further characterization of this response will provide an understanding of the mechanisms of pathogenesis of extracellular matrix (ECM) and the potential role of metalloproteinases in tissue remodeling after injury.
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PMID:Matrix metalloproteinase expression in cytokine stimulated human dermal fibroblasts. 1292 75

Chronic hypoxia is implicated in lung fibrosis, which is characterized by enhanced deposition of extracellular matrix (ECM) molecules. Transforming growth factor-beta (TGF-beta) plays a key role in fibroblast homeostasis and is involved in disease states characterized by excessive fibrosis, such as pulmonary fibrosis. In this study, we investigated if hypoxia modulates the effects of TGF-beta on the expression of gelatinases: matrix metalloproteinase (MMP)-2 and MMP-9, interstitial collagenases: MMP-1 and MMP-13, tissue inhibitors of MMP (TIMP), collagen type I and interleukin-6 (IL-6). Primary human lung fibroblasts, established from tissue biopsies, were cultivated under normoxia or hypoxia in the presence of TGF-beta1, TGF-beta2 or TGF-beta3. Gelatinases were assessed by gelatin zymography and collagenases, TIMP, collagen type I and IL-6 by ELISA. Under normoxia fibroblasts secreted MMP-2, collagenases, TIMP, collagen type I and IL-6. TGF-betas significantly decreased MMP-1 and increased TIMP-1, IL-6 and collagen type I. Hypoxia significantly enhanced MMP-2, and collagenases. Compared to normoxia, the combination of TGF-beta and hypoxia reduced MMP-1, and further amplified the level of TIMP, IL-6, and collagen type I. Thus, in human lung fibroblasts hypoxia significantly increases the TGF-betas-induced secretion of collagen type I and may be associated to the accumulation of ECM observed in lung fibrosis.
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PMID:Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts. 1456 88

The trichothecene mycotoxin deoxynivalenol (DON) induces IgA hyperelevation and mesangial IgA deposition in mice that mimics the early stages of human IgA nephropathy (IgAN). Among potential mediators of this disease, interleukin-6 (IL-6) is likely to play a particularly critical role in IgA elevation and disease exacerbation. Based on previous findings that dietary fish oil (FO) suppresses DON-induced IgAN, we hypothesized that FO inhibits the induction of IL-6 expression by this mycotoxin in vivo and in vitro. Mice were fed modified AIN 93G diet amended with 7% corn oil (CO) or with 1% corn oil plus 6% menhaden fish oil (FO) for up to 8 weeks and then exposed acutely to DON by oral gavage. DON-induced plasma IL-6 and splenic mRNA elevation in FO-fed mice were significantly suppressed after 8 weeks when compared to the CO-fed group. The effects of FO on phosphorylation of mitogen-activated protein kinases (MAPKs), critical upstream transducers of IL-6 up-regulation, were also assessed. DON-induced phosphorylation of extracellular signal regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) was significantly suppressed in spleens of mice fed with FO, whereas p38 was not. Splenic COX-2 mRNA expression, which has been previously shown to enhance DON-induced IL-6, was also significantly decreased by FO, whereas plasma levels of the COX-2 metabolite, prostaglandin E2, were not affected. To confirm in vivo findings, the effects of pretreatment with the two primary n-3 PUFAs in FO, eicosapentaenoic acid (20:5[n-3]; EPA) and docosahexaenoic acid, (22:6[n-3]; DHA), on DON-induced IL-6 expression were assessed in LPS-treated RAW 264.7 macrophage cells. Consistent with the in vivo findings, both EPA and DHA significantly suppressed IL-6 superinduction by DON, as well as impaired DON-induced ERK1/2 and JNK1/2 phosphorylation. In contrast, the n-6 PUFA arachidonic acid (20:4[n-3]) had markedly less effects on these MAPKs. Taken together, the capacity of FO and its component n-3 PUFAs to suppress IL-6 expression as well as ERK 1/2 and JNK 1/2 activation might explain, in part, the reported suppressive effects of these lipids on DON-induced IgA nephropathy.
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PMID:Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. 1469 Jul 64

There is ample evidence supporting the view that alterations in the balance between matrix deposition and matrix degradation brought about by changes in the respective activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) contribute significantly to cardiac dysfunction and disease. Here we show that TIMP-1 was upregulated up to threefold after treatment with the inflammatory mediator and gp130 ligand oncostatin M (OSM) in human adult cardiac myocytes and fibroblasts. The Erk1/2 inhibitor PD98059 and the p38 inhibitor SD202190 abolished the effect of OSM on TIMP-1 production in both cell types. Human cardiac myocytes and human cardiac fibroblasts also express MMP-1, 2, 3 and 9, and TIMP-2 constitutively. OSM, however, did not affect the expression of these proteins. In addition also the other gp130 ligands tested, cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) had no effect on the expression of TIMPs and MMPs studied. We speculate that OSM by inducing TIMP-1 expression counteracts excessive proteolysis and unrestricted matrix degradation during inflammatory processes in the heart. The notion that OSM favors matrix stabilization in the human heart is further supported by our earlier observation that OSM also upregulates PAI-1, the physiological inhibitor of the protease urokinase-type PA (u-PA), which in turn is essential for extracellular proteolysis. Therefore we propose a role for the gp130 ligand OSM in the modulation of cardiac remodeling and repair processes.
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PMID:The gp130 ligand oncostatin M regulates tissue inhibitor of metalloproteinases-1 through ERK1/2 and p38 in human adult cardiac myocytes and in human adult cardiac fibroblasts: a possible role for the gp130/gp130 ligand system in the modulation of extracellular matrix degradation in the human heart. 1589 Mar 57

Tumor embolism occurs in 30 to 50% of all cases of cardiac myxoma, but the causes are still uncertain. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the extracellular matrix (ECM) and play a crucial role in plaque instability and aortic aneurysm development, in addition to cancer and heart failure. To determine whether MMP activity contributes to tumor embolism, we examined 27 left atrium-sided myxomas, 10 of which showed clinical signs of peripheral embolism. Immunohistochemistry (in all cases) and Western blotting, and in situ and in-gel zymography (in four embolic and six nonembolic consecutive tumors) demonstrated higher expression and activity of MT1-MMP, pro-MMP-2, and pro-MMP-9 in embolic myxomas, whereas pro-MMP-1, MMP-3, and TIMP-1 levels were similar to those of nonembolic tumors. Reverse transcriptase-polymerase chain reaction demonstrated that increased MMP activity was due, at least in part, to increased transcription and that TIMP-2 transcripts increased in embolic myxomas. In vitro, embolic tumor cells retained higher MT1-MMP and pro-MMP-2 levels in basal conditions and after stimulation with interleukin-1beta and interleukin-6. Increased MMP synthesis and release correlated with enhanced ECM degradation products containing glycosaminoglycan chains in embolic myxoma tissue. Our results strongly suggest that MMP overexpression may contribute to an excessive degradation of tumor ECM and increase the risk of embolism in cardiac myxomas.
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PMID:Increased expression and activity of matrix metalloproteinases characterize embolic cardiac myxomas. 1592 Jan 47

The enzyme group of matrix metalloproteinases (MMPs) and their inhibitors, so-called tissue inhibitors of matrix-metalloproteinases (TIMPs), are crucial mediators responsible for wound repair after parenchymal damage. Little is known about the role of MMPs and TIMPs in severe sepsis. The aim of the present study was therefore to investigate their levels in patients with severe sepsis and to examine their association with prognosis. MMP-2, MMP-9, TIMP-1, TIMP-2 and interleukin-6 (IL-6) plasma levels were measured by ELISA methods in 37 patients on day 1 of severe sepsis. 37 healthy volunteers served as controls. Levels of MMP-9, TIMP-1, TIMP-2 and IL-6 in septic patients were significantly higher compared to healthy controls (p<0.001), whereas MMP-2 levels were not different in patients and controls. TIMP-1 levels were significantly higher in non-survivors (4675+/-435 ng/ml, mean+/-SEM) compared to survivors of severe sepsis (3201+/-249 ng/ml; p<0.01). Septic patients with TIMP-1 values >3200 ng/ml were 4.5 times more likely to die than patients with lower values (RR = 4.5; 95% CI 1.14-17.6, p = 0.014). Our results indicate that MMP-9, TIMP-2 and TIMP-1 are elevated in severe sepsis. Furthermore, TIMP-1 may serve as a useful laboratory marker to predict the clinical outcome of patients presenting with severe sepsis.
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PMID:Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. 1700 30

The tissue inhibitor of metalloproteinases (TIMP)-1 is a multifunctional protein which is not only an inhibitor of matrix metalloproteinases (MMPs) but also to have a possible "cytokine-like" action. Here, we first compared mRNA expression of TIMP-1 and MMP-9 in BEL-7402 (a hepatocellular carcinoma cell line), L-02 (a normal liver cell line) and QSG-7701 (a cell line derived from peripheral tissue of liver carcinoma) using real-time quantitative RT-PCR. By evaluating the variation of the MMP-9/TIMP-1 ratio as an index of reciprocal changes of the expression of the two genes, we observed that the MMP-9/TIMP-1 ratio was about 13- and 5-fold higher in BEL-7402 than in L-02 and QSG-7701, respectively. Significantly, overexpression of TIMP-1 decreased the MMP-9/TIMP-1 ratio in BEL-7402 and then inhibited the cell growth to 60% and reduced the migration to about 30%. Meanwhile, our data showed that interleukin-6 (IL-6) (100 ng/mL) could also inhibited the cell growth of BEL-7402. Further studies indicated that TIMP-1 mediated the inhibitory effect of IL-6 on BEL-7402 cell proliferation in a STAT3-dependent manner, which could further accelerate the expression of the cyclin-dependent kinase inhibitor p21. A dominant negative STAT3 mutant totally abolished IL-6-induced TIMP-1 expression and its biological functions. The present results demonstrate that TIMP-1 may be one of the mediators that regulate the inhibitory effect of IL-6 on BEL-7402 proliferation in which STAT3 signal transduction and p21 up-regulation also play important roles.
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PMID:TIMP-1 mediates the inhibitory effect of interleukin-6 on the proliferation of a hepatocarcinoma cell line in a STAT3-dependent manner. 1746 23

Breast milk is a primary source of nutrition that contains many endogenous compounds that may affect infant development. The goals of this study were to develop reliable assays for selected endogenous breast milk components and to compare levels of those in milk and serum collected from the same mother twice during lactation (2-7 weeks and 3-4 months). Reliable assays were developed for glucose, secretory IgA, interleukin-6, tumor necrosis factor-a, triglycerides, prolactin, and estradiol from participants in a US EPA study called Methods Advancement in Milk Analysis (MAMA). Fresh and frozen (-20 degrees C) milk samples were assayed to determine effects of storage on endogenous analytes. The source effect (serum vs milk) seen in all 7 analytes indicates that serum should not be used as a surrogate for milk in children's health studies. The authors propose to use these assays in studies to examine relationships between the levels of milk components and children's health.
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PMID:Assays for endogenous components of human milk: comparison of fresh and frozen samples and corresponding analytes in serum. 1747 67


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