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  • 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.
    Author: Mehindate K, al-Daccak R, Aoudjit F, Damdoumi F, Fortier M, Borgeat P, Mourad W.
    Journal: Lab Invest; 1996 Oct; 75(4):529-38. PubMed ID: 8874384.
    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.
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