Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KE-298 is a novel antirheumatic drug which suppresses various animal models of arthritis by inhibiting the production of inflammatory cytokines. In a phase II study of rheumatoid arthritis patients, ingestion of KE-298 led to significant improvements in the Lansbury index. The objective of the present study was to clarify the effects of KE-298 against synovium functions, using rheumatoid arthritis synoviocytes. We investigated the effects of KE-298 on the production of matrix metalloproteinases and tissue inhibitor-1 of metalloproteinases and bone absorptive mediators including interleukin (IL)-6 and prostaglandin (PG) E2 in tumor necrosis factor (TNF)-alpha-stimulated rheumatoid arthritis synoviocytes. Rheumatoid arthritis synoviocytes were obtained from knee joints of rheumatoid arthritis patients and type B fibroblast-like synoviocytes were stimulated with TNF-alpha, with or without KE-298. The contents of metalloproteinases and tissue inhibitor-1 of metalloproteinases and IL-6 and PGE2 in culture media were measured by enzyme-linked immunosorbent assay. KE-298 significantly suppressed TNF-alpha-induced production of promatrix metalloproteinase-1 and IL-6, in a dose-dependent manner, but not that of tissue inhibitor-1 of metalloproteinases. The potential of KE-298 to suppress the production of matrix metalloproteinase-1 and IL-6 may explain its efficacy on rheumatoid arthritis.
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PMID:Suppressive effects of the new antirheumatic drug KE-298 on TNF alpha-induced production of matrix metalloproteinases but not of tissue inhibitor-1 of metalloproteinases in human rheumatoid synoviocytes. 967 46

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) produced by monocytes are believed to be involved in the migration of these cells through the basement membrane and the ensuing destruction of connective tissue in chronic inflammatory lesions. Because monocytes encounter a variety of cytokines at these sites, we examined the effect of cytokines either alone or in combination on the production of monocyte MMPs and TIMP-1. TNF-alpha, granulocyte-macrophage-CSF (GM-CSF), or IL-1 beta when added individually enhanced the endogenous levels of 92-kDa gelatinase (MMP-9) and TIMP-1 but failed to induce interstitial collagenase (MMP-1). However, GM-CSF, when added with either TNF-alpha or IL-1 beta, induced MMP-1 and synergistically enhanced MMP-9 and TIMP-1. Th2 cytokines, such as IL-4, inhibited the induction of MMPs and TIMP-1 by TNF-alpha, GM-CSF, and IL-1. Cytokine stimulation of MMP-1 was due, at least in part, to an increase in the release of arachidonic acid and PG E2 (PGE2), because inhibition of MMP-1 by indomethacin could be reversed by exogenous PGE2. In contrast to MMP-1, cytokine stimulation of MMP-9 and TIMP-1 was unaffected by indomethacin. The PGE2-independent induction of monocyte MMP-9 and TIMP-1 by these cytokines differed from stimulation of MMP-9 and TIMP-1 by LPS, which is in large part PG-dependent. In addition, LPS stimulated higher levels of MMP-1 whereas cytokines induced higher levels of MMP-9 and TIMP-1. This is the first demonstration that monocyte MMP-1 can be induced by cytokines and that MMP-1, MMP-9, and TIMP-1 are differentially regulated by cytokines through PG-dependent and -independent mechanisms.
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PMID:Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms. 974 73

It is well recognized that burn trauma induces an inflammatory cascade and the release of cytokines including tumor necrosis factor (TNF)-alpha. The negative inotropic effects of TNF-alpha on the heart are well recognized, but the cellular mechanisms remain unclear. To examine one aspect of cellular function, we exposed cardiac myocytes isolated from NZW rabbits (collagenase digestion) to either TNF-alpha (200, 400, or 1000 U/mL) or sham or burn plasma (10% by volume) for 3 to 4 h and measured calcium transient ratios in the isolated, contracting myocytes using the fluorescent indicator Fura-2-acetoxymethyl (1.2 microM); myocytes treated with media alone served as controls. Cells were placed in a perfusion chamber on the stage of an inverted Nikon microscope and superfused with buffer at 37 degrees C and stimulated at 1 Hz. A Tracor Northern Fluoroplex 1000 microspectrofluorometer and camera system, set to provide excitation of 340 and 380 nm with emission at 450-580 nm, was used to measure Ca2+ transients during systole-diastole. [Ca2+]i was reported as a fluorescence ratio (F340/F380) to minimize effects of different cell thickness and motion artifacts. After recording diastolic/systolic [Ca2+]i, cells were stimulated with isoproterenol, and [Ca2+]i was again measured. TNF-alpha produced diastolic and systolic [Ca2+]i values (1.067 +/- .023/1.301 +/- .017) that were similar to values seen after myocyte exposure to burn plasma (1.099 +/- .024/1.307 +/- .028) and significantly greater than values measured in controls (.857 +/- .017/1.077 +/- .015, p < .05). Our data confirm that burn trauma and TNF-alpha alter calcium handling by cardiomyocytes. The possible contribution of altered intracellular calcium dynamics to cardiac contractile abnormalities after burn trauma and TNF-alpha administration warrants further study.
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PMID:Burn trauma and tumor necrosis factor alpha alter calcium handling by cardiomyocytes. 978 59

In rheumatoid arthritis, T lymphocytes have been proposed to play a pivotal role in the disease process, but they have also been considered to simply represent an epiphenomenon in a primarily synoviocyte/macrophage-driven disease. To directly examine the contribution of CD4 T cells in synovitis, T cells were either depleted from or adoptively transferred into NOD-SCID mice engrafted with rheumatoid synovial tissue. Injection of anti-CD2 antibody resulted in the elimination of 80-90% of tissue-infiltrating T cells in the synovial grafts and was followed by a marked decline in the production of IL-1beta (loss of 70%), TNF-alpha (loss of 86%), and IL-15 (loss of 84%) mRNA. Also, transcription of MMP-1 and MMP-2 was reduced by 72% in anti-CD2-treated chimeras. Immunohistochemistry demonstrated that the cytokines and proteases derived mostly from CD68(+) synovial cells, which disappeared from the tissue upon T cell depletion. Adoptive transfer of autologous tissue-derived T cell lines and T cell clones into synovium-SCID mouse chimeras augmented the production of IFN-gamma as well as TNF-alpha in the synovial infiltrates. Administration of IFN-gamma in small doses to anti-CD2-treated chimeras restored the survival and the functional activity of CD68(+) synovial cells. In vitro studies confirmed the critical role of synovial T cells and IFN-gamma in the survival of synovial CD68(+) cells. These data demonstrate that the production of proinflammatory cytokines and of tissue-degrading enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease.
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PMID:Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. 988 54

Growth of and metalloproteinase production by fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) contribute to cartilage and bone destruction associated with development of the expanding inflammatory tissue referred to as pannus. Increased levels of extracellular matrix (ECM) proteins in the pannus suggest that intracellular signals generated through integrin receptors might control these processes. We developed a cell culture system permitting accurate assessment of the effect of cell adhesion to various ECM proteins on FLS phenotype. We show that FLS proliferation to platelet-derived growth factor requires a second signal provided by adhesion to an ECM protein. Fibronectin, vitronectin, collagen, or laminin could provide the second signal and was similarly required for the proliferation of FLSs from RA or osteoarthritis patients. Adhesion to fibronectin, collagen, or Arg-Gly-Asp peptide down-regulated collagenase expression. Primarily alphav integrin receptors mediated this down-regulation upon adhesion to fibronectin. Loss of cell adhesion and TNF-alpha stimulation synergistically increased collagenase expression. Increased collagenase expression upon nonadherence was mimicked by treatment with cytochalasin B, suggesting that the loss of cytoskeletal structure associated with a change in cell shape mediates increased collagenase in nonadherent cells. Thus, although increased fibronectin in the lining layer in RA might be expected to inhibit collagenase expression, the change in cell shape associated with this multilayer structure might actually lead to increased collagenase expression.
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PMID:Integrin engagement regulates proliferation and collagenase expression of rheumatoid synovial fibroblasts. 997 41

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.
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PMID:Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? 1020 82

The pleiotropic cytokine tumor necrosis factor (TNF)-alpha has been implicated in the mechanism of ovulation. Experiments were designed to test the hypothesis that TNF-alpha secreted from the oocyte-cumulus cell complex stimulates follicular collagenase production and thereby contributes to ovarian wall degradation and ovulatory rupture. Proestrous ewes were treated with GnRH to synchronize the onset of the gonadotropin surge; ovulation occurs approximately 24 h later. There was an increase in TNF-alpha (immunoassay) in antral fluid of preovulatory follicles at 18 h after GnRH, which was related to tissue collagenolytic bioactivity (radiolabeled type I substrate digestion by enzymatic extract) and collagen (hydroxyproline) depletion. Intrafollicular injection of TNF-alpha antibodies at 12 h after GnRH negated the rise in follicular collagenolytic bioactivity (and is known to block ovulation in the sheep). Moreover, collagenase production was enhanced when follicular tissues (0 h GnRH) were incubated (6 h) with recombinant TNF-alpha; this effect was abolished by the transcriptional inhibitor actinomycin D. Secretion of TNF-alpha by oocyte-cumulus cell complexes isolated from preovulatory follicles simulated the in vivo circumstance. Immunostaining indicated that TNF-alpha was confined mainly to the oocyte before GnRH administration, accumulated in cumulus cells during the mid-to-late preovulatory period, and was expended with the imminent approach of ovulation. To our knowledge, this is the first report specifying that up-regulation of collagenase expression is a target mode of TNF-alpha action in preovulatory follicles. The oocyte-cumulus cell complex is an apparent source of soluble TNF-alpha.
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PMID:Tumor necrosis factor alpha regulates collagenolytic activity in preovulatory ovine follicles: relationship to cytokine secretion by the oocyte-cumulus cell complex. 1057 6

To elucidate the mechanism of neutrophil dysfunction in patients with maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), intracellular enzyme activity such as oxidative burst, elastase, cathepsin, and collagenase, was investigated. Response of enzyme activity to in vitro addition of TNF-alpha, which is known to have a powerful priming effect on neutrophils, was also evaluated. Peripheral blood from 15 HD and 15 CAPD patients was washed and incubated with Cell Probe, an indicator for intracellular enzyme activity. Mean fluorescent intensity of neutrophils, which represents neutrophil enzyme activity, was measured by flowcytometry. In HD group, unstimulated enzyme activity was similar to that of control, but activity after addition of TNF-alpha was significantly lower than the control. In the group of CAPD, enzyme activity without stimulation was not different from that of control, and in TNF-alpha stimulated neutrophils, only elastase activity was lower than control. Many of the enzyme activities after stimulation were lower in HD than in CAPD. Response to in vitro addition of TNF-alpha was diminished in both dialysis groups, but more prominent in HD neutrophils. Duration of dialysis, serum concentration of beta 2-microglobulin (beta 2-MG) and parathyroid hormone (PTH) was significantly related inversely to intracellular enzyme activity in HD patients. To the contrary, in CAPD group, although beta 2-MG and PTH showed similar negative correlation, duration of dialysis was not related to enzyme activity. These results indicate that neutrophils in patients with maintenance dialysis have diminished intracellular oxidative burst, elastase, and cathepsin activity. Especially, impaired response to TNF-alpha closely related to neutrophil dysfunction in dialysis patients.
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PMID:[Flowcytomeric analysis on neutrophil intracellular enzyme activity in patients on hemodialysis and continuous ambulatory peritoneal dialysis]. 1069 98

Endometriosis, a benign gynecologic disorder, occurs in about 10% of women in reproductive age and in up to 50% of women with infertility. The basic etiologic factors causing this disease are unknown as yet. Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix (ECM). Their proteolytic activity is regulated by tissue inhibitors of metalloproteinases (TIMPs). Tumor necrosis factor-alpha converting enzyme (TACE) is a membrane-bound disintegrin metalloproteinase that processes the membrane-associated cytokine proTNF-alpha to its mature soluble form. TNF-alpha induces the secretion of several MMPs. In order to study the expression of MMP-1, -2, -3 and -9, TIMP-1 and -2, TACE and TNF-alpha in endometrium and endometriotic tissue, we investigated formalin-fixed paraffin sections of endometriotic tissues and normal endometrium with immunohistochemical techniques and in situ hybridisation. Furthermore, quantitative PCR was used for quantification of TACE-mRNA in fresh tissue. We found in this study significant higher protein expression of MMP-1 and TACE and significant lower protein expression of TMP-1 and -2 in endometriotic tissue compared to endometrium. This data may suggest that high TACE expression causes the increased conversion of membrane-bound proTNF-alpha into its soluble form, which stimulates the increased secretion of MMP-1. The simultaneous deficiency of TIMP-1 and -2 in endometriotic tissue suppose an additional proteinase inhibitor imbalance in endometriosis.
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PMID:Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis. 1084 74

We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.
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PMID:Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. 1086 17


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