title: Induction of stromelysin gene expression by tumor necrosis factor alpha is inhibited by dexamethasone, salicylate, and N-acetylcysteine in synovial fibroblasts.
abstract: Proinflammatory cytokines, altered connective tissue metabolism, and overexpression of matrix metalloproteinases (MMPs) such as stromelysin compared to tissue inhibitors of metalloproteinases (TIMPs) result in synovial inflammation and erosion of arthritic cartilage. Tumor necrosis factor alpha (TNF-alpha) is a major synovial inflammatory mediator responsible for inhibiting extracellular matrix (ECM) synthesis and stimulating degradation of cartilage ECM by activated MMPs in arthritic joints. To suppress these effects and to gain insight into the mechanism of TNF-alpha action, we identified the inhibitors of TNF-alpha stimulation of stromelysin gene expression. In bovine synovial fibroblasts, TNF-alpha did not affect a recently identified inhibitor, TIMP-3, but induced stromelysin mRNA expression in a dose- and time-dependent fashion (3- to 5-fold) which required de novo protein synthesis. Stimulation by TNF-alpha was potently inhibited (99-100%) by the synthetic glucocorticoid, dexamethasone. Sodium salicylate dose-dependently inhibited (100%) the TNF-alpha action. Indomethacin and ibuprofen were partially inhibitory. Free radical scavenger antioxidant, N-acetylcysteine (but not other antioxidants) also suppressed the TNF-alpha induction (36-100%) of stromelysin suggesting involvement of reactive oxygen species in the induction process. TNF-alpha induction of stromelysin gene expression can therefore be inhibited at the gene expression level by several pharmacological agents which are likely to function via arachidonic acid metabolites, free radical scavenging or interference with the activator protein 1, polyoma virus enhancer A-binding protein 3, and nuclear factor kappaB classes of transcription factors. Our results may help to elucidate the mechanism of TNF-alpha action and explain the beneficial role of these agents in the treatment of inflammatory diseases.
authors.affiliation: Louis-Charles Simard Research Centre, Centre Hospitalier de L'Université de Montréal Campus Notre-Dame, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Morin
authors.forename: W Q
authors.initials: WQ
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Su
authors.forename: M
authors.initials: M
authors.lastname: Ahmad
authors.forename: M
authors.initials: M
authors.lastname: Zafarullah
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012980:Sodium Salicylate / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013859:Thiocarbamates / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D013859:Thiocarbamates; D019717:Tissue Inhibitor of Metalloproteinase-3; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D014810:Vitamin E; D003907:Dexamethasone; D011392:Proline; D019278:Matrix Metalloproteinase 3; D001205:Ascorbic Acid; D012980:Sodium Salicylate; D007052:Ibuprofen; D000111:Acetylcysteine; D007213:Indomethacin