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)

Transforming growth factor beta (TGF-beta) is usually associated with matrix formation and tissue repair; in contrast, cellular expression of the serine proteinase, urokinase-type plasminogen activator (u-PA) is often correlated with tissue remodeling, as well as with cell migration and transformation. We report here that purified recombinant human TGF-beta (greater than or equal to 300 pg/ml) can stimulate rapidly (within 2 h) the u-PA activity of nonrheumatoid synovial fibroblast-like cells. As for interleukin 1 (IL-1), u-PA mRNA levels are raised in response to TGF-beta, but unlike IL-1, no increase in prostaglandin E2 levels occurs. In contrast to a number of other examples in the literature, in which these two cytokines have opposing actions, TGF-beta can potentiate the action of optimal concentrations of IL-1 in enhancing u-PA expression. These effects of TGF-beta are similar to those of all-trans-retinoic acid. In addition, synovial fibroblast DNA synthesis was stimulated by TGF-beta. Because TGF-beta has been detected in the synovia of patients with rheumatoid arthritis and has been shown to reduce the collagenase levels and proliferation of synovial fibroblast-like cells, it has been proposed by others to be involved beneficially in the reparative processes occurring in arthritic lesions. However, on the basis of our findings, we propose alternative functions for this cytokine--namely, roles in the destructive events as well as in the synovial hyperplasia observed in rheumatoid joints.
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PMID:Transforming growth factor beta stimulates urokinase-type plasminogen activator and DNA synthesis, but not prostaglandin E2 production, in human synovial fibroblasts. 190 92

Joints with rheumatoid arthritis are a site for chronic inflammation involving T cells, B cells, macrophages and dendritic cells. When these cells interact cytokines are likely to be produced. The presence of different cytokines in the synovial fluid of patients with rheumatoid arthritis has been studied and the macrophage derived cytokines such as IL-1, IL-6, TNF-alpha, TGF-beta and PDGF have usually been detected in large quantities, whereas T cell produced cytokines (IL-2, IL-4, IFN-gamma) are absent or present in small quantities. IL-1, IL-6 and TNF-alpha have several functions which suggest that they participate in the chronic disease process of rheumatoid arthritis, such as increasing production of eicosanoid, collagenase and prostaglandin E2. Many synovial B cells are activated and produce large amounts of immunoglobulins. We searched for a B cell stimulatory activity in rheumatoid synovial fluid and found a B cell differentiation and helper activity. Cytokines in the joints of patients with rheumatoid arthritis seem central for the propagation of the disease process. Specific intervention in cytokine production or in its effects might help to relieve symptoms in rheumatoid patients.
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PMID:Cytokines in rheumatoid arthritis. 193 Sep 11

In the present study, we sought to identify the T cell-replacing factor which selectively induces IgG2b antibody formation in lipopolysaccharide-activated mouse spleen cells in vitro and in vivo, and which is present in the synovial fluid (SF) of rheumatoid arthritis (RA) patients. The protein A plaque assay was used to measure IgM, IgG1, IgG2b, and IgG3 plaque-forming cells. An enzyme-linked immunosorbent assay was used to measure interleukin-6 (IL-6) levels in RA SF. We found that IgG2b induction by RA SF is not caused by IL-6, IL-1, or any other inflammatory cytokines or mediators, such as transforming growth factor beta, platelet-derived growth factor, nerve growth factor, fibroblast growth factor, epidermal growth factor, elastase, collagenase, and phospholipase A2. IgG2b-inducing factor in RA SF has unique biological properties compared with those of the interleukins and inflammatory mediators known to be present in RA SF.
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PMID:Relationship between IgG2b-inducing activity in rheumatoid arthritis synovial fluid and other well-known cytokines and inflammatory mediators. 195 23

The aim of the present study was to determine whether interleukin 1 alpha (Il-1), a cytokine known to have a stimulatory effect on collagenase production, also influences the phagocytosis and intracellular digestion of collagen fibrils by fibroblasts. Mouse long bones and calvariae both with surrounding periosteum were cultured for 24 or 48 hours in media containing varying concentrations of the cytokine. The periostea were subjected to morphometric analysis in order to assess the volume density of phagocytosed collagen fibrils in fibroblasts. The results indicated that neither in calvarial nor in long bone periosteum the uptake and intracellular degradation of collagen by fibroblasts was influenced by Il-1. However, between both tissues the amount of collagen phagocytosed differed considerably. It appeared that within 48 hours periosteal fibroblasts of calvariae ingested at least three times more fibrillar collagen than those of long bone periosteum. This finding suggests intrinsic differences between these connective tissues as to the phagocytic behaviour of the fibroblasts. Analysis of collagenase activity in the media demonstrated that under the influence of Il-1 collagenase release increased about 1.5- to 2-fold, most of the enzyme being in a latent form. The media also proved to contain an inhibitor of collagenase, its production not being affected by Il-1. It is concluded that under the conditions tested Il-1 does not seem to play a role in the regulation of the intracellular pathway of collagen digestion.
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PMID:Interleukin 1 increases the production of collagenase but does not influence the phagocytosis of collagen fibrils. 196 17

The effects of recombinant human Interleukin-1 alpha (IL-1 alpha), Interleukin-1 beta (IL-1 beta), and Tumor Necrosis Factor-alpha (TNF-alpha) on collagen biosynthesis were studied in vitro using dermal fibroblast cultures. Both forms of IL-1 and TNF-alpha induced a dose-dependent inhibition of both types I and III collagen synthesis, as measured by radioimmunoassay, gel electrophoresis, or collagenase-sensitive material. This effect was accompanied by a significant release of prostaglandin E2 into the culture medium. However, indomethacin, a potent inhibitor of prostaglandin synthesis, could not prevent the inhibitory effect of the three cytokines on collagen synthesis. Measurement of type I and type III procollagen mRNA levels in IL-1 treated cells revealed that both IL-1 alpha and IL-1 beta were potent enhancers of procollagen gene expression at pretranslational level. On the other hand, TNF-alpha was found to reduce the steady-state levels of type I and III procollagen mRNA in a dose-dependent manner. Quantitation of IL-1 beta and TNF-alpha transcripts following TNF-alpha treatment of fibroblasts indicated that this cytokine can induce IL-1 beta gene expression in these cells. By contrast, TNF-alpha mRNA remained at a constant level after TNF-alpha exposure. These data suggest that IL-1 and TNF-alpha, two cytokines that share several biologic activities, modulate collagen deposition in dermal fibroblasts by mechanisms that are clearly different: TNF-alpha appears to act at a transcriptional level to inhibit collagen synthesis, whereas IL-1 inhibitory action involves important translational regulation, still unknown, that counterbalances its stimulatory effect on procollagen mRNA levels. Moreover, our data suggest the existence of local fibroblastic cytokine production that may be involved in the modulation of extracellular matrix deposition.
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PMID:Comparative effects of interleukin-1 and tumor necrosis factor-alpha on collagen production and corresponding procollagen mRNA levels in human dermal fibroblasts. 199 84

Recombinant human interleukin-1 alpha (IL-1 alpha) induced a time-dependent (0-72 hours) and concentration-dependent (0.01-10 ng/ml) production of metalloproteinases (collagenase, gelatinase, stromelysin) and prostaglandin E2 (PGE2) in rabbit articular chondrocytes (RAC). Exposure of RAC to recombinant human platelet-derived growth factor homodimer BB (PDGF-BB; 2-200 ng/ml) in the presence of stimulatory and substimulatory concentrations of IL-1 alpha resulted in a marked augmentation of metalloproteinase and PGE2 production. PDGF-BB exerted no agonist effects on RAC responsiveness. PDGF-BB up-regulated the number of IL-1 receptors per chondrocyte but had no effect on receptor affinity. Cycloheximide and actinomycin D caused a concentration-dependent suppression of the PDGF-BB-mediated potentiation of radiolabeled IL-1 alpha binding to RAC and cell responsiveness to IL-1 alpha. Similarly, IL-1 increased the number of PDGF receptors on RAC without changing receptor affinity. These data are discussed within the context of cytokine-growth factor interactions as components of the pathogenesis of arthritic diseases.
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PMID:Platelet-derived growth factor potentiates cellular responses of articular chondrocytes to interleukin-1. 205 15

Human monocytes cultured on adherent IgG produce a specific IL-1 inhibitor that functions as a receptor antagonist (IL-1ra). This molecular has been purified, sequenced, cloned as a cDNA, and expressed in Escherichia coli. Recombinant IL-1ra has 17,000 mol wt and binds to IL-1 receptors on T lymphocytes, synovial cells, and chondrocytes with an affinity nearly equal to that of IL-1. These studies have examined some biological properties of purified recombinant human IL-1ra. This protein exhibits a dose-responsive inhibition of Il-1 alpha and Il-1 beta augmentation of PHA-induced murine thymocyte proliferation. The recombinant IL-1ra also blocks IL-1 alpha and IL-1 beta stimulation of PGE2 production in human synovial cells and rabbit articular chondrocytes, and of collagenase production by the synovial cells. A 50% inhibition of these IL-1-induced biological responses requires amounts of IL-1ra up to 100-fold in excess of the amounts of IL-1 alpha or IL-1 beta present. IL-1ra may play an important role in normal physiology or in pathophysiological states by functioning as a natural IL-1 receptor antagonist in the cell microenvironment.
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PMID:Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. 213 69

A subpopulation of cells was derived from the Hs431 connective tissue sarcoma cell line which possessed high affinity (estimated Kd = 0.38-0.55 nM) binding sites for human recombinant [125I]-IL-1 alpha. Binding at 4 degrees C was slow approaching equilibrium by 4 hrs. Dissociation of [125I]-IL-1 alpha was also slow and unaffected by high concentrations of cold ligand. The binding site also underwent ligand-induced internalization at 37 degrees C. An Mr = 83,000 protein was identified in affinity crosslinking studies. Despite these similarities to previously reported IL-1 receptors, Hs431 cells did not exhibit biological responses to IL-1 which have been observed in other cell lines. IL-1 did not induce PGE2 or collagenase synthesis. IL-1 also failed to induce ornithine decarboxylase activity (ODC) or stimulate [3H]-thymidine incorporation. In contrast, the Hs431 cells did contain a functional epidermal growth factor (EGF) receptor as determined from binding studies, protein kinase activity, induction of ODC, and stimulation of [3H]-thymidine incorporation. Thus, the refractoriness of Hs431 cells to IL-1 was fairly specific and did not result from a generalized defect associated with cell transformation.
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PMID:Characterization of a high affinity interleukin-1 (IL-1) specific binding site in a human synovial sarcoma (Hs431) cell line. 216 29

Previous studies showed that acute administration of O,O,S trimethyl phosphorothioate (OOS-TMP), a contaminant in malathion, acephate and fenitrothion, led to increases in metabolic activities, such as, secretion of interleukin 1 and nonspecific esterase, of splenic and peritoneal macrophages. In this report, the effect of OOS-TMP administration on the levels of the neutral proteases, elastase, collagenase and plasminogen activator, in cultures supernatants of peritoneal and splenic macrophages is presented. Acute administration of OOS-TMP elevated collagenase levels only at day 3 following treatment with 10 or 20 mg/kg OOS-TMP. Levels of elastase in culture supernatant of peritoneal and splenic macrophages, on the other hand, was elevated at days 1, 3, 5 and 7 following administration of OOS-TMP. The effect on elastase secretion was dose-dependent at days 5 and 7 after treatment. Levels of plasminogen activator activity in the culture supernatants of splenic macrophages was elevated at day 5 following treatment with both doses of OOS-TMP. At days 1 and 3, the level of plasminogen activator inhibitor was suppressed. However, at days 5 and 7 plasminogen activator inhibitory activity was close to control values. These data show that OOS-TMP administration led to an elevation in the levels of neutral proteases in culture supernatants of peritoneal and splenic macrophages. This elevation indicates that acute OOS-TMP administration alters another parameter of macrophage function, which is elevated following exposure to acute inflammatory stimuli.
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PMID:Modulation of macrophage protease activity by acute administration of O,O,S trimethyl phosphorothioate. 216 Jan 88

An in vitro model is used to investigate the hypothesis that activated fibroblasts produce collagenolytic activity in inflammatory sites. Interleukin-1, a cytokine present in the gingiva and crevicular fluid of periodontitis patients, has multiple biologic activities including the ability to stimulate collagenase in dermal and synovial fibroblasts. In this report IL-1 is tested on gingival (GF) and periodontal ligament fibroblasts (PLF) for its ability to increase collagenolytic activity and procollagenase mRNA and protein. GF produce a 3- to 7-fold increase in collagenase activity, while PLF collagenase activity is rarely increased above control amounts by IL-1 treatment. In contrast, both cell types demonstrate an increase in procollagenase protein production with IL-1 treatment. RNA from both GF and PLF contain procollagenase mRNA as demonstrated when northern blots of fibroblast total RNA are hybridized with the cDNA for human procollagenase. Treatment with IL-1 increases the steady-state levels of this message in GF by up to 10-fold in 48 hours when measured with dot blot analysis standardized for poly-A RNA. PLF also produce up to 7 times more message at the same dose and time. Since fibroblasts present in the lesion are exposed to inflammatory cell products it is possible that the production of collagenase by these cells could result in the destruction of the periodontal fibrous attachment.
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PMID:Interleukin-1 regulation of procollagenase mRNA and protein in periodontal fibroblasts in vitro. 216 52


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