Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vivo, fibroblasts reside in connective tissues, with which they communicate in a reciprocal way. Such cell--extracellular matrix interactions can be studied in vitro by seeding fibroblasts in collagen lattices. Depending upon the mechanical properties of the system, fibroblasts are activated to assume defined phenotypes. In the present study, we examined a transcriptional profile of primary human dermal fibroblasts cultured in a relaxed collagen environment and found relative induction (>2-fold) of 393 out of approx. 7100 transcripts when compared with the same system under mechanical tension. Despite down-regulated proliferation and matrix synthesis, cells did not become generally quiescent, since they induced transcription of numerous other genes including matrix metalloproteinases (MMPs) and growth factors/cytokines. Of particular interest was the induction of gene transcripts encoding pro-inflammatory mediators, e.g. cyclo-oxygenase-2 (COX-2), and interleukins (ILs)-1 and -6. These are apparently regulated in a hierarchical fashion, since the addition of IL-1 receptor antagonist prevented induction of COX-2, IL-1 and IL-6, but not that of MMP-1 or keratinocyte growth factor (KGF). Our results suggest strongly that skin fibroblasts are versatile cells, which adapt to their extracellular environment by displaying specific phenotypes. One such phenotype, induced by a mechanically relaxed collagen environment, is the 'pro-inflammatory' fibroblast. We propose that fibroblasts that are embedded in a matrix environment can actively participate in the regulation of inflammatory processes.
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PMID:Expression of pro-inflammatory markers by human dermal fibroblasts in a three-dimensional culture model is mediated by an autocrine interleukin-1 loop. 1468 80

The signaling mechanism by which the anti-inflammatory cytokine IL-10 mediates suppression of proinflammatory cytokine synthesis remains largely unknown. Macrophage-specific STAT3-null mice have demonstrated that STAT3 plays a critical role in the suppression of LPS-induced TNF-alpha release, although the mechanism by which STAT3 mediates this inhibition is still not clear. Using an adenoviral system, we have expressed a dominant negative (DN) STAT3 in human macrophages to broaden the investigation to determine the role of STAT3 in IL-10-mediated anti-inflammatory signaling and gene expression. Overexpression of STAT3 DN completely inhibited IL-10-induced suppressor of cytokine signaling 3, tissue inhibitor of MMP-1, TNF receptor expression, and the recently identified IL-10-inducible genes, T cell protein tyrosine phosphatase and signaling lymphocyte activation molecule. STAT3 DN also blocked IL-10-mediated inhibition of MHC class II and COX2 expression. In agreement with the studies in STAT3-null mice, overexpression of the STAT3 DN completely reversed the ability of IL-10 to inhibit LPS-mediated TNF-alpha and IL-6 production. However, real-time PCR analysis showed that STAT3 DN expression did not affect immediate suppression of TNF-alpha mRNA, but did reverse the suppression observed at later time points, suggesting a biphasic regulation of TNF-alpha mRNA levels by IL-10. In conclusion, although STAT3 does appear to be the dominant mediator of the majority of IL-10 functions, there are elements of its anti-inflammatory activity that are STAT3 independent.
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PMID:Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. 1468 68

The purpose of this study was to examine the source of adipokines released by the visceral and sc adipose tissues of obese humans. Human adipose tissue incubated in primary culture for 48 h released more prostaglandin E(2), IL-8, and IL-6 than adiponectin, whereas the release of plasminogen activator inhibitor 1 and hepatocyte growth factor was less than that of adiponectin but greater than that of leptin. IL-10 and TNFalpha were released in amounts less than those of leptin, whereas vascular endothelial growth factor and IL1-beta were released in much lower amounts. The accumulation of adipokines was also examined in the three fractions (adipose tissue matrix, isolated stromovascular cells, and adipocytes) obtained by collagenase digestion of adipose tissue. Over 90% of the adipokine release by adipose tissue, except for adiponectin and leptin, could be attributed to nonfat cells. Visceral adipose tissue released greater amounts of vascular endothelial growth factor, IL-6, and plasminogen activator inhibitor 1 compared with abdominal sc tissue. The greatly enhanced total release of TNFalpha, IL-8, and IL-10 by adipose tissue from individuals with a body mass index of 45 compared with 32 was due to nonfat cells. Furthermore, most of the adipokine release by the nonfat cells of adipose tissue was due to cells retained in the tissue matrix after collagenase digestion.
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PMID:Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. 1472 44

Inflammatory foci are rich in proteases released by neutrophils (serine proteases) and macrophages (metalloproteases). These enzymes can degrade extracellular matrix proteins and cell membrane bound proteins thus contributing to the development and progression of inflammatory reaction. In this study we have investigated the influence of collagenase (metalloprotease) and trypsin (serine protease) on murine resident and oil-induced peritoneal macrophages (Mf). Short in vitro treatment of Mf, not affecting cell viability, significantly reduced the release of reactive oxygen intermediates (ROIs) and at the same time triggered the increase of IL-6 production and to lesser extent of TNF-alpha production. Both these effects were dependent on enzyme concentration used and were particularly well pronounced in resident macrophages. In addition both enzymes cleaved a number of cell-membrane molecules, including CD23, CD14, CD95L, and Mac-3. We hypothesize that the enzymatic digestion of certain Mf surface receptor proteins in inflammatory foci may be responsible for modification of cell behaviour either by preventing the generation of specific signal or alternatively by delivering a mock substitute signal to the cell interior. In effect inhibition of ROIs production limits their destructive effects and the increase in the secretion of IL-6 stimulates the synthesis of acute phase proteins and triggers other anti-inflammatory mechanisms thus directing Mf present in inflammatory foci into regulatory pathway rather than allowing them to perform solely the effector function.
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PMID:Modulation of macrophage activity by proteolytic enzymes. Differential regulation of IL-6 and reactive oxygen intermediates (ROIs) synthesis as a possible homeostatic mechanism in the control of inflammation. 1476 Sep 41

VEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, interleukin (IL)-1beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha) were measured in culture supernatants by enzyme-linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR-2 mRNA was quantified by real-time reverse transcription-polymerase chain reaction and the protein was identified by immuno-gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen-activated protein kinases ERK 1/2, and long-lasting activation of the transcription factor AP-1 (activator protein-1). VEGF increased secreted MMP-1, MMP-3, and especially MMP-13, which could be effectively reduced by an inhibitor of VEGFR-2 kinase activity. Interestingly, VEGF diminished the expression of TIMP-1 and especially TIMP-2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL-1beta, IL-6, TNF-alpha, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis.
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PMID:Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. 1499 3

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.
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PMID:Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes. 1501 31

SW982 cells are characterized by expression of inflammatory cytokine and matrix metalloproteinase (MMP) genes and by their response to dexamethasone at different cell densities. They express genes encoding interleukin (IL)-1 beta; IL-6; transforming growth factor-beta; intercellular adhesion molecule-1; cycloxygenase (COX)-2; and MMPs, including MMP-1, MMP-2, MMP-13, and MT1-MMP; tissue inhibitor of metalloproteinase-2; and a disintegrin and metalloproteinase with thrombospondin motifs-4. Expression of all the genes examined was induced with 2 ng/ml IL-1 beta at low cell density. The cells, however, failed to express tumor necrosis factor-alpha, COX-1, and MMP-9, regardless of the presence of IL-1 beta. Dexamethasone significantly reduced IL-1 beta, IL-6, COX-2, and MMP-1 expression at high cell density. The results suggest that SW982 cells are a useful tool for studying the expression of inflammatory cytokine or MMP genes.
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PMID:Phenotypic characterization of a human synovial sarcoma cell line, SW982, and its response to dexamethasone. 1503 80

There is increasing evidence that abnormal cytokine expression and increased metalloproteinase activity are implicated in the pathophysiology of acute coronary syndromes. This study investigates the serum profiles of representative metalloproteinases (MMP-1, -2, -9) and their tissue inhibitor (TIMP-1) in patients with myocardial infarction (MI) and unstable angina (UA) in relation to circulating proinflammatory cytokine (TNF-alpha and IL-6) activity. Furthermore, we examined the effects of a 30-day treatment with atorvastatin on serum levels of these inflammatory factors. Serum concentrations of MMP-1, -2, -9, TIMP-1, IL-6 and TNF-alpha were measured (enzyme-linked immunosorbent assay (ELISA) method) in 23 acute myocardial infarction patients and 20 unstable angina patients on 0 day, 1st, 3rd, 7th and 30th day after admission. Sixteen normal volunteers were used as healthy controls. Additionally, 12 patients of myocardial infarction group and 11 patients of unstable angina group were treated with atorvastatin (20 mg/day) for 30 days in a randomized design. In patients with myocardial infarction and unstable angina, serum levels of MMP-2, -9, TIMP-1, TNF-alpha and IL-6 were significantly higher than those of healthy controls in all time frames (p<0.05). In the group of unstable angina patients, we observed a statistically significant reduction in the levels of MMP-9, TIMP-1 and IL-6 after the 30-day atorvastatin administration. Our results suggest that serum MMPs, TIMP-1 and proinflammatory cytokines play an important role in the pathophysiology of the acute coronary syndromes. The reduction of these factors by short-term atorvastatin administration may provide a new insight into the pleiotropic effects of statins on unstable coronary artery disease.
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PMID:Serum profiles of matrix metalloproteinases and their tissue inhibitor in patients with acute coronary syndromes. The effects of short-term atorvastatin administration. 1509 92

A Chlorella powder was screened using 52 in vitro assay systems for enzyme activity, receptor binding, cellular cytokine release, and B and T cell proliferation. The screening revealed a very potent inhibition of human protein tyrosine phosphatase (PTP) activity of CD45 and PTP1C with 50% inhibitory concentration (IC(50)) values of 0.678 and 1.56 microg/mL, respectively. It also showed a moderate inhibition of other PTPs, including PTP1B (IC(50) = 65.3 microg/mL) and T-cell-PTP (114 microg/mL). Other inhibitory activities and their IC(50) values included inhibition of the human matrix metalloproteinases (MMPs) MMP-1 (127 microg/mL), MMP-3 (185 microg/mL), MMP-7 (18.1 microg/mL), and MMP-9 (237 microg/mL) and the human peptidase caspases caspase 1 (300 microg/mL), caspase 3 (203 microg/mL), caspase 6 (301 microg/mL), caspase 7 (291 microg/mL), and caspase 8 (261 microg/mL), as well as release of the cytokines interleukin (IL)-1 (44.9 microg/mL), IL-2 (14.8 microg/mL), IL-4 (49.2 microg/mL), IL-6 (34.7 microg/mL), interferon-gamma (31.6 microg/mL), and tumor necrosis factor-alpha (11 microg/mL) from human peripheral blood mononuclear cells. Chlorella also inhibited B cell proliferation (16.6 microg/mL) in mouse splenocytes and T cell proliferation (54.2 microg/mL) in mouse thymocytes. The binding of a phorbol ester, phorbol 12,13-dibutyrate, to its receptors was also inhibited by Chlorella with an IC(50) of 152 microg/mL. These results reveal potential pharmacological activities that, if confirmed by in vivo studies, might be exploited for the prevention or treatment of several serious pathologies, including inflammatory disease and cancer.
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PMID:Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding. 1529 60

Interactions between members of the TNF ligand superfamily with their cognate TNF receptors play a crucial role in maintaining immune homeostasis in normal individuals, while dysregulation of certain TNF-ligands and receptors contributes to the pathogenesis of autoimmunity. Identification of novel members of the TNF ligand and receptor families will promote our understanding of the pathogenesis of systemic autoimmune diseases, thus facilitating the development of novel therapeutic approaches. TNF-like weak inducer of apoptosis (TWEAK), a recently identified member of the TNF ligand family, induces PGE2, MMP-1, IL-6, IL-8, RANTES, and IP-10 in fibroblasts and synoviocytes, and upregulates ICAM-1, E-selectin, IL-8, and MCP-1 in endothelial cells. The receptor for TWEAK, Fn14, is expressed in various organs including the kidney; it is intriguing that some of these chemokines induced by TWEAK are crucial in the pathogenesis of lupus nephritis. Furthermore, others have described upregulated TWEAK expression on the surface of T cells in human lupus. In this paper we review the possible roles of TWEAK/TWEAK receptor interactions in the pathogenesis of inflammatory and systemic autoimmune diseases, with particular focus on systemic lupus erythematosus. TWEAK blockade may be helpful therapeutically in restoration of tolerance, but is more likely to modify inflammatory damage in target organs.
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PMID:The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. 1535 86


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