Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK506, a neutral macrolide with immunosuppressive properties, was shown to selectively and rapidly inhibit the accumulation of IL-2 mRNA, as well as the mRNAs of other early (E) phase T cell activation genes such as IL-3, IL-4, GM-CSF, TNF alpha, IFN-gamma, and c-myc in activated human peripheral blood T cells. The activity of FK506, when compared to Cyclosporin A, another immunosuppressant, was 10 to 100x more potent in its ability to inhibit IL-2 mRNA synthesis. FK506 inhibited IL-2 mRNA accumulation in Con A, Con A plus PMA, Ionomycin plus PMA, anti-CD3, and anti-CD3 plus PMA activated T cells. Transcripts from other T cell gene classes such as the immediate early (IE) phase gene, c-fos, the late phase (L) genes, transferrin receptor, IL-2R alpha-chain, and TNF-beta, and the constitutive class genes glyceraldehyde-3-phosphate dehydrogenase and class I MHC HLA-B7 were not affected by FK506. The macrolide Rapamycin, which is structurally related to FK506, had no inhibitory effect on IE, E, L, or constitutive class mRNAs, but it appeared to increase the levels of the E-phase transcripts that were inhibited in FK506 treated T cells. The effect of FK506 on inducible genes in non-T and non-lymphoid human cells was studied in LPS-induced monocytes and PMA or IL-1 activated synovial fibroblasts. FK506 did not affect expression of the mRNAs for IL-1 alpha or IL-1 beta in human monocytes, or of stromelysin, collagenase, or TIMP in synovial fibroblasts. Nuclear run-off transcription studies indicate that FK506 inhibits transcription of the IL-2 gene. These studies suggest that Cyclosporin A and FK506 may effect a common early event in the T cell activation pathway.
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PMID:The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. 247 51

Exposure to synovial factors or purified interleukin-1 (IL-1) induces the production of prostaglandin E2 (PGE2) and the neutral proteinases (NP) collagenase, gelatinase and stromelysin by lapine articular chondrocytes. Having frequently found our partially purified synovial preparations to elicit this process of chondrocyte activation more strongly than recombinant IL-1, Phadke's report of synergism between IL-1 and fibroblast growth factor (FGF) intrigued us. In our hands, basic FGF (1 ng/ml-1 micrograms/ml) did not activate chondrocytes but, in a dose-dependent manner, enhanced the production of PGE2 and NP by chondrocytes exposed to IL-1 alpha or IL-1 beta (1-10 U/ml). Further examination determined that the basic FGF was a better synergist than acidic FGF. In view of reports that FGF activates protein kinase C, we tested whether phorbol myristate acetate (PMA) could substitute for FGF as a synergist. Not only did it do so, but PMA alone (0.1 ng/ml-100 ng/ml), unlike FGF, provoked the production of PGE2 by chondrocytes. The Ca2+ ionophore A23187 could not substitute for FGF in enhancing induction of the NP. Using a cDNA probe, we confirmed that the synergistic effects of both FGF and PMA upon IL-1 mediated collagenase induction, were associated with an increased abundance of collagenase mRNA.
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PMID:Chondrocyte activation by interleukin-1: synergism with fibroblast growth factor and phorbol myristate acetate. 255 71

Stromelysin is a member of a gene family of metalloproteinases involved in extracellular matrix remodeling in normal and diseased processes. Primary cultures of rheumatoid synovial cells produce large amounts of metalloproteinase mRNA and proteins. We cloned a cDNA for human stromelysin from a rheumatoid synovial cell cDNA library, and we used the cDNA to isolate the gene for human stromelysin and a related gene, stromelysin 2. We sequenced parts of the genes and found that both are contained on approximately 14 kilobase pairs of DNA. Using an exon-containing fragment of the stromelysin 2 genomic clone as a specific probe in Northern blot analysis, we demonstrate the differential expression of stromelysin and stromelysin 2 in rheumatoid synovial cells, human foreskin fibroblasts, and rabbit synovial fibroblasts. In addition, using chimeric constructs of the stromelysin promoter linked to the bacterial gene chloramphenicol acetyltransferase (CAT), we show that the elements required for the tumor promoter phorbol myristate acetate (PMA), epidermal growth factor (EGF), and interleukin 1 beta (IL-1 beta) induction are contained on a 307 base pair fragment which includes approximately 270 base pairs (bp) of 5'-flanking DNA. The cloning of the human stromelysin and stromelysin 2 genes, the documentation of their differential expression, and the identification of transcriptional regulatory regions in the stromelysin gene will facilitate the study of metalloproteinase gene expression in normal processes and in diseases such as rheumatoid arthritis.
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PMID:Cloning of the genes for human stromelysin and stromelysin 2: differential expression in rheumatoid synovial fibroblasts. 260 16

We have determined that human stromelysin mRNA can be induced by interleukin-1 beta (IL-1 beta) and that the induced mRNA levels can be suppressed by retinoic acid and dexamethasone (Saus, J., Quinones, S., Otani, Y., Nagase, H., Harris, E.D., Jr., and Kurkinen, M. (1988) J. Biol. Chem. 263, 6742-6745). Here we show, by nuclear run-on and transient gene expression analyses, that IL-1 beta induction is a promoter function and that dexamethasone suppresses IL-1 beta-induced gene activity. For transient gene expression assays, 1.3 kilobase pairs of the stromelysin promoter region (-1303 to -11 relative to the transcription start site) and shorter fragments thereof were cloned into a human growth hormone reporter vector. In transfected human fibroblast cultures all the constructs, with the exception of the one containing the shortest promoter fragment (-53 to -11), responded to IL-1 beta induction. Interestingly, the ability of IL-1 beta to induce human growth hormone expression decreased as the length of the promoter fragment was reduced. Dexamethasone treatment suppressed the induced human growth hormone levels by approximately 50% irrespective of the promoter length. These results suggest that the 1.3-kilobase pairs stromelysin promoter fragment contains DNA elements required for IL-1 beta induction and dexamethasone suppression.
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PMID:Transcriptional regulation of human stromelysin. 278 89

Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, collectively termed the nitric oxide synthases. We investigated the role of NO. in the modulation of two metal-dependent proteolytic enzymes (collagenase and stromelysin) which are activated during inflammatory and infective arthritis. The inflammatory mediators interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and the bacterial cell wall fragment endotoxin, induced both nitric oxide synthase activity and stromelysin and collagenase activity in whole cell preparations and in conditioned media from explants of bovine and human cartilage. Both NO2- (the stable end-product of NO.) and metalloprotease activity were inhibited by competitive inhibitors of nitric oxide synthase. The NO. donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP) also induced metalloprotease activity in a dose-dependent fashion. These data provide evidence that NO. plays a regulatory role in the activation of metal-dependent proteases in articular chondrocytes and cartilage.
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PMID:Nitric oxide activates metalloprotease enzymes in articular cartilage. 752 96

The expression of the matrix-degrading enzymes collagenase and stromelysin is modulated by a variety of biologic and pharmacologic agents. IFN-gamma has potent effects on metalloproteinase production and therefore may play an important role in preventing excessive connective tissue degradation during inflammation and repair. We investigated the mechanisms of collagenase and stromelysin regulation by IFN-gamma in human dermal fibroblasts. IFN-gamma (300 U/ml) prevented the stimulation of metalloproteinase gene expression by IL-1 beta. In addition, incubation of fibroblasts with IFN-gamma resulted in a marked increase in cellular indoleamine 2,3-dioxygenase (IDO) mRNA, a > 90% depletion of tryptophan, and a corresponding > 30-fold increase in the tryptophan metabolite kynurenine in the culture media. Reducing the concentration of tryptophan from 25 microM to 0 markedly diminished the ability of fibroblasts to increase collagenase and stromelysin mRNA and collagenase production in response to IL-1 beta. Addition of exogenous tryptophan (25-50 micrograms/ml) to cultures that had been tryptophan depleted by pretreatment with IFN-gamma for 48 h restored the fibroblast response to IL-1 beta or PMA, but had no effect on IFN-gamma-induced HLA-DR alpha chain mRNA expression. These results indicate that inhibition of collagenase and stromelysin gene expression by IFN-gamma in fibroblasts is associated with activation of IDO and enhanced cellular tryptophan metabolism. Tryptophan degradation and ensuing tryptophan depletion may account, at least in part, for the inhibitory effect of IFN-gamma on metalloproteinase production in dermal fibroblasts.
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PMID:Inhibition of collagenase and stromelysin gene expression by interferon-gamma in human dermal fibroblasts is mediated in part via induction of tryptophan degradation. 761 20

Cytokines and proteases are thought to play a role in the destruction of cartilage and the development of osteoarthritis. The purpose of this study was to document chronological involvement of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), stromelysin (MMP-3), fibronectin, and alteration in the chondroitin sulphate sulfation pattern. Canine patellae underwent a closed-joint impact to induce the development of osteoarthritis. The animals were killed at 2, 12, 24, and 52 weeks. The patellar damage included cracks in the superficial zone of cartilage and the zone of the calcified cartilage-bone interface, vertical step-off fractures in the zone of calcified cartilage, and loss of proteoglycan around the cracks in the deep and superficial zones of cartilage. With avidin-biotin immunohistochemistry, these specimens were stained with antibodies to IL-1 beta, TNF-alpha, MMP-3, fibronectin, and altered proteoglycan sulfate with the monoclonal antibody 3-B-3. Three of the four specimens obtained at 2 weeks demonstrated a strong cellular and weak matrix staining pattern for IL-1 beta, TNF-alpha, MMP-3, and fibronectin around the cracks in the superficial and transitional zones of cartilage. No consistent staining pattern was noted in the cracks in the deep zone. None of the specimens obtained at 12, 24, or 52 weeks stained for these antibodies. No staining for the abnormal sulfation with the 3-B-3 antibody was evident in any specimen. The specimens obtained at 52 weeks showed healing of the step-off fractures and a filling-in of the proteoglycan loss. This model probably reflects the short-term cartilaginous changes in the patella after trauma; thus, only transient elevations in the cytokines and proteases were evident.
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PMID:Immunolocalization of selected cytokines and proteases in canine articular cartilage after transarticular loading. 768 74

The objective of this paper was to study the effects of interleukin 4 (IL-4) and interleukin 6 (IL-6) on cartilage matrix degradation, the production of chondroitin-4-sulphate (C4S) and chondroitin-6-sulphate (C6S), metalloproteinase (stromelysin 1 = MMP-3) and metalloproteinase inhibitor (TIMP-1) production. Cartilage matrix degradation was assayed the release of 35SO4 from chondrocyte cultures. TIMP-1 and MMP-3 were measured by ELISA. C6S and C4S were measured by HPLC analysis. IL-1 beta significantly enhanced C4S production and significantly suppressed C6S production. Thus, the C4S/C6S ratio was significantly enhanced by IL-1 beta, and significantly suppressed by IL-4. IL-4 removed the suppressing effects of IL-1 beta for C6S and the enhancing effects of IL-1 beta for the C4S/C6S ratio. Whereas IL-1 beta stimulated the production of MMP-3, IL-4 and IL-6 had no effect on enzyme activity. IL-4, but not IL-6, removed the enhancing effects of IL-1 beta for MMP-3. In contrast, IL-4 and IL-6 significantly enhanced TIMP-1 production in chondrocytes, IL-4, but not IL-6, also significantly suppressed IL-1 beta-mediated cartilage matrix degradation. On the other hand, IL-6 significantly suppressed spontaneous cartilage matrix degradation which is supposed to be mediated by the autocrine IL-1 mechanisms. In conclusion our results suggest that IL-4 and IL-6 both protect the cartilage matrix degradation induced by IL-1.
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PMID:The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. 770 54

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

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


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