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)

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.
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PMID:Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. 775 12

It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase and that such degradation is regulated by metalloproteinase inhibitors. In the present study, the effects of IL-6 and oxygen radical scavengers on cartilage matrix degradation were studied. Superoxide dismutase, catalase, or methionine all significantly inhibited cartilage matrix degradation both in IL-1 beta-stimulated and unstimulated experimental conditions. Both 10 mM EDTA and 100 nM tissue inhibitor of metalloproteinase (TIMP) significantly inhibited cartilage matrix degradation. The addition of methionine significantly inhibited collagenase activity produced in the culture supernatants of chondrocytes stimulated with IL-1 beta. IL-6 significantly suppressed cartilage matrix degradation produced spontaneously or by IL-1 beta stimulation in chondrocytes. IL-6 inhibited superoxide production by chondrocytes both in IL-1 beta-stimulated or unstimulated conditions. These results suggest that oxygen radicals are involved in cartilage matrix degradation mediated by both paracrine and autocrine IL-1 mechanisms and that oxygen radical-mediated activation of collagenase in chondrocytes may explain the mechanisms of how oxygen radicals are involved in cartilage matrix degradation. IL-6 inhibited superoxide production in chondrocytes and thus inhibited cartilage matrix degradation.
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PMID:Role of oxygen radicals and IL-6 in IL-1-dependent cartilage matrix degradation. 784 4

In the present study, we demonstrate that both interleukin-1 (IL-1) and interleukin-6 (IL-6) induced a significant decrease in glycosaminoglycan (GAG) synthesis and, more strikingly, secretion by 7 and 13 day-old chick embryo skin fibroblasts. We demonstrated that interleukin treatment also inhibited the synthesis of collagenase-digestible proteins (type I collagen). In addition, tissue culture supernatants (conditioned media, CM) were tested for reactivity for IL specific ELISAs and for their ability to stimulate proliferative responses in mouse thymocytes and hybridoma cells. Our findings demonstrate that chick embryo skin fibroblasts spontaneously produce IL-1 and, in even greater amounts, IL-6. Highest levels of interleukin secretion were found in the CM of 13 day-old fibroblasts and the IL-1 beta isoform was predominant over IL-1 alpha. Pretreatment of the fibroblasts with either IL-1 or IL-6 increased the secretion of both cytokines. Increased IL-1 levels were correlated with enhanced IL-1 bioactivity in the CM of IL-6 treated fibroblasts. By contrast, the raised concentrations of IL-1 in the CM of IL-1 treated cells and IL-6 in the CM of IL-1 or IL-6 treated fibroblasts failed to translate into augmented bioactivity. These observations, taken together, indicated that IL-1 and IL-6 are able to regulate the synthesis and secretion of ECM macromolecules of developing connective tissues and the cytokine release by chick embryo skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 and interleukin-6 differentially regulate the accumulation of newly synthesized extracellular matrix components and the cytokine release by developing chick embryo skin fibroblasts. 784 37

Inflammatory bone resorption, a characteristic feature of periodontal disease and rheumatoid arthritis, appears to be mediated by interleukin-1 beta (IL-1 beta). IL-1 beta has been shown to stimulate a wide range of proteolytic enzymes, including collagenases and plasminogen activators, in particular chondrocytes, synovial cells, and isolated osteoblasts. In this study, we have examined the hypothesis that IL-1 beta may stimulate bone loss by inducing the activity of plasminogen activators (PAs) in bone cultures. The latter would convert plasminogen to plasmin, which in turn can activate precursor procollagenase to collagenase. Active collagenase would then break down the bone collagen matrix. In the present study, release of 45Ca from fetal rat long bones in culture was studied in the presence of plasminogen and IL-1 beta. Plasminogen and IL-1 beta separately enhance resorption of fetal rat long bones in vitro. When plasminogen and IL-1 beta are added together at suboptimal levels, mainly additive effects are observed. The presence of heat-inactivated serum does not alter these results. These data tend to indicate that IL-1 beta is stimulating bone resorption through both PA-dependent and PA-independent pathways.
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PMID:Effects of plasminogen and interleukin-1 beta on bone resorption in vitro. 784 4

To examine the effects of interleukin-1 beta (IL-1 beta) on collagenase production by human periodontal ligament fibroblasts (PLF) and gingival fibroblasts (GF) in culture, collagenase activity in conditioned media was determined using a novel procedure that circumvented interference by enzyme inhibitors. Fibroblasts obtained from five paired periodontal ligament and gingival tissues were cultured for two weeks, and then incubated for a further 72 h in alpha-MEM supplemented with various concentrations of IL-1 beta (0 to 1250 pg/ml). The conditioned media from individual cultures were harvested and treated with dithiothreitol to inactivate TIMPs, and then with APMA, to activate the latent collagenase. Collagenase activity was measured fluorometrically using FITC-collagen as a substrate. IL-1 beta induced a approximately 2.4 to 5.2-fold increase in collagenase activity in PLF compared to a approximately 1.4 to 2.2-fold increase in GF. These results are in contrast to previous studies in which collagenase activity was measured in the presence of TIMPs, and indicate that PLF are more sensitive to IL-1 beta than GF. Since both PLF and GF are present in periodontal lesions, it is possible that collagenase secretion stimulated by exposure to inflammatory cell products such as IL-1 beta may participate in the destruction of collagen fibers involved in periodontal attachment.
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PMID:Interleukin-1 beta stimulates collagenase production by cultured human periodontal ligament fibroblasts. 787 78

Previous studies have shown that the production of interstitial collagenase by rat myometrial smooth muscle cells is dependent on serotonin. These cells fail to produce collagenase early in culture, however, and produce the enzyme only 8-12 days after confluence. During the early quiescent period, collagenase production can be induced by low concentrations of bacterial endotoxin. Under these conditions, interleukin (IL)-1 alpha and IL-1 beta mRNAs increase coincident with collagenase and collagenase mRNA. Serotonin removal decreases IL-1 alpha and IL-1 beta mRNAs, and effect that is rapidly reversed upon readdition of serotonin. Conversely, serotonin-dependent increases in IL-1 mRNAs are blocked by progesterone. Experiments with 5-HT2 receptor agonists and antagonists indicate that induction is mediated by the 5-HT2 receptor subtype. In serotonin-treated cells late in culture, IL-1 mRNAs increase coincident with the production of collagenase. Similarly, exogenous IL-1 fully substitutes for lipopolysaccharide in stimulating myometrial cells to produce collagenase early in culture. Cells treated with IL-1 receptor antagonist fail to make IL-1 mRNAs or collagenase but produce collagenase and IL-1 mRNAs following antagonist removal. These results indicate that serotonin-dependent IL-1 production by the myometrial cell is required for collagenase production and that IL-1 participates in its own production via an autocrine mechanism.
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PMID:Serotonin regulation of interleukin-1 messenger RNA in rat uterine smooth muscle cells. Relationship to the production of interstitial collagenase. 796 54

Leukotriene C4 (LTC4), a mediator generated by a variety of inflammatory cells, participates in several physiological and pathological processes. It has been shown that LTC4 stimulates collagen synthesis by fibroblasts, suggesting a role in collagen turnover. However, the possible effect of this mediator on collagen degradation has not been examined. In this study we explored the role of LTC4 in the modulation of fibroblast interstitial collagenase and TIMP-1. Confluent cultures of three human normal lung fibroblast cell lines, and one derived from idiopathic pulmonary fibrosis (IPF) were exposed to LTC4 0.1, 1 and 10 nM, and to IL-1 beta as positive control. Collagenase and TIMP mRNAs expression were analyzed by Northern blot followed by densitometric scanning. Immunoreactive procollagenase was detected by immunoblot, and collagenase activity was measured using [3H]collagen. Our results showed that LTC4 enhanced several-fold collagenase mRNA expression in collagenase-producing fibroblasts, and induced the expression of the enzyme mRNA in collagenase-nonproducing fibroblasts, both in normal and IPF derived cell lines. LTC4 1 nM induced the highest response. Collagenolytic activity and immunoreactive collagenase paralleled collagenase mRNA expression. Interestingly, simultaneous exposure of fibroblasts to LTC4 plus IL-1 failed to show additive effects. Moreover, in two cell lines the combination resulted in a decrease of collagenase mRNA expression compared with both mediators separately. TIMP mRNA levels were not significantly modified by LTC4, nor IL1 beta. Our findings suggest that LTC4 plays a role in the modulation of fibroblast collagenase, and it may participate in extracellular matrix remodeling during lung inflammation.
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PMID:Leukotriene C4 upregulates collagenase expression and synthesis in human lung fibroblasts. 798 Dec 29

Interleukin-1 beta is believed to contribute to the pathophysiology of rheumatoid arthritis by activating collagenase gene expression. We have used a cell culture model of rabbit synovial fibroblasts to examine the molecular mechanisms of IL-1 beta-mediated collagenase gene expression. Stimulation of rabbit synovial fibroblasts with 10 ng/ml recombinant human IL-1 beta resulted in a 20-fold increase in collagenase mRNA by 12 h. Transient transfection studies using collagenase promoter-CAT constructs demonstrated that proximal sequences responded poorly to IL-1 beta, possibly due to insufficient activation of AP-1 by this cytokine. More distal sequences were required for IL-1 beta responsiveness, with a 4700 bp construct showing approximately 5-fold induction above control. To examine post-transcriptional mechanisms, transcript from a human collagenase cDNA was constitutively produced by the simian virus 40 early promoter. IL-1 beta stabilized the constitutively expressed human transcript. Furthermore, mutation of the ATTTA motifs in the 3' untranslated region of the human gene also stabilized the transcript. Finally, the rabbit collagenase 3' untranslated region destabilized a constitutively transcribed chloramphenicol acetyltransferase transcript. These data indicate that in addition to activating transcription, IL-1 beta increases collagenase transcript stability by reversing the destabilizing effects of sequences in the 3' untranslated region.
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PMID:Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms. 798 35

Immortalized human chondrocytes were established by transfection of primary cultures of juvenile costal chondrocytes with vectors encoding simian virus 40 large T antigen and selection in suspension culture over agarose. Stable cell lines were generated that exhibited chondrocyte morphology, continuous proliferative capacity (> 80 passages) in monolayer culture in serum-containing medium, and expression of mRNAs encoding chondrocyte-specific collagens II, IX, and XI and proteoglycans in an insulin-containing serum substitute. They did not express type X collagen or versican mRNA. These cells synthesized and secreted extracellular matrix molecules that were reactive with monoclonal antibodies against type II collagen, large proteoglycan (PG-H, aggrecan), and chondroitin-4- and chondroitin-6-sulfate. Interleukin-1 beta (IL-1 beta) decreased the levels of type II collagen mRNA and increased the levels of mRNAs for collagenase, stromelysin, and immediate early genes (egr-1, c-fos, c-jun, and jun-B). These cell lines also expressed reporter gene constructs containing regulatory sequences (-577/+3,428 bp) of the type II collagen gene (COL2A1) in transient transfection experiments, and IL-1 beta suppressed this expression by 50-80%. These results show that immortalized human chondrocytes displaying cartilage-specific modulation by IL-1 beta can be used as a model for studying normal and pathological repair mechanisms.
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PMID:Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes. 798 69

Cyclosporin A is successfully used in the treatment of scleroderma, a condition with excessive deposition of collagen in the dermis. Cultured human dermal fibroblasts were used as a model to study the effects of cyclosporin A on metalloproteinase expression and activity. Fibroblasts were treated with collagenase inducing agents, phorbol 12-myristate 13-acetate (PMA), cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and the calcium ionophore A23187 in the presence of cyclosporin A under serum-free conditions, and alterations in metalloproteinase expression were studied by Northern hybridization and immunoblotting analyses, and assays for collagenolytic activity. Induction of collagenase expression by PMA and cytokines was enhanced severalfold by 1-10 microM cyclosporin A. Treatment of cells with cyclosporin A alone caused only a minor increase in collagenase mRNA levels. The secretion of immunoreactive collagenase protein and the level of p-aminophenylmercuric acetate activatable collagenase activity were increased by PMA and further enhanced by cyclosporin A. The expression of the other metalloproteinases stromelysin-1, 92-kD gelatinase, and 72-kD gelatinase or metalloproteinase inhibitor TIMP-1 were not affected by cyclosporin A. Time dependence analysis of the expression of the mRNAs for c-jun and junB indicated that the induction of these genes persisted significantly longer in cells treated with both PMA and cyclosporin A than in cells treated with PMA alone. Enhanced induction of collagenase mRNA may thus result from prolonged AP-1 activity. The results indicate that cyclosporin A potently enhances the expression of collagenase in dermal fibroblasts.
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PMID:Cyclosporin A enhances cytokine and phorbol ester-induced fibroblast collagenase expression. 800 58


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