title: Interleukin-4, transforming growth factor beta 1, and dexamethasone inhibit superantigen-induced prostaglandin E2-dependent collagenase gene expression through their action on cyclooxygenase-2 and cytosolic phospholipase A2.
abstract: Signalling via MHC class II in human fibroblast-like synoviocytes selectively induces interstitial collagenase gene expression over its natural inhibitor, the tissue inhibitor of metalloproteinase (TIMP), through a prostaglandin E2 (PGE2)-dependent pathway involving cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2). In the present study, we investigated the effect of three different agents the T-cell-derived cytokine IL-4, transforming growth factor beta 1 (TGF-beta 1), and dexamethasone (DXS) on this response. Our results indicate that treatment of superantigen-stimulated synoviocytes with DXS or IL-4 inhibited collagenase gene expression without affecting TIMP gene expression. In contrast, treatment of superantigen-stimulated synoviocytes with TGF-beta 1 resulted in an inhibition of collagenase induction and an increase in TIMP gene expression. IL-4, TGF-beta 1, and DXS abolished PGE2 production and the expression of COX-2 and cPLA2 but failed to affect the constitutive expression of COX-1 and secreted PLA2. Moreover, all agents abolished protein production and phosphorylation of COX-2 and cPLA2, respectively. The inhibitory effect of the three agents on collagenase gene expression was partially reversed by exogenous PGE2, which confirms that major histocompatibility complex class II-induced collagenase gene expression is regulated through a PGE2-mediated pathway. These data highlight a mode of action of a classical anti-inflammatory agent (DXS) and of two cytokines with recognized anti-inflammatory characters (IL-4 and TGF-beta 1) on a major histocompatibility complex class II-induced response and support the involvement of COX-2 and cPLA2 in major histocompatibility complex class II-induced interstitial collagenase production in human fibroblast-like synoviocytes.
authors.affiliation: Centre de Recherche en Rhumatologie et Immunologie, Université Laval, Ste-Foy, Québec, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Mehindate
authors.forename: R
authors.initials: R
authors.lastname: al-Daccak
authors.forename: F
authors.initials: F
authors.lastname: Aoudjit
authors.forename: F
authors.initials: F
authors.lastname: Damdoumi
authors.forename: M
authors.initials: M
authors.lastname: Fortier
authors.forename: P
authors.initials: P
authors.lastname: Borgeat
authors.forename: W
authors.initials: W
authors.lastname: Mourad
mesh_terms: D001172:Arthritis, Rheumatoid / Q000473:pathology; D017364:Collagenases / Q000235:genetics*; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects; D008565:Membrane Proteins; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D018089:Superantigens / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D018089:Superantigens; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D017364:Collagenases; D015232:Dinoprostone