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.

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 E 2 (PGE 2 )-dependent pathway involving cyclooxygenase-2 (COX-2) and cytosolic phospholipase A 2 (cPLA 2 ). In the present study, we investigated the effect of three different agents : the T-cell-derived cytokine IL-4, transforming growth factor β1 (TGF-β1), 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-β1 resulted in an inhibition of collagenase induction and an increase in TIMP gene expression. IL-4, TGF-β1, and DXS abolished PGE 2 production and the expression of COX-2 and cPLA 2 but failed to affect the constitutive expression of COX-1 and secreted PLA 2 . Moreover, all agents abolished protein production and phosphorylation of COX-2 and cPLA 2, respectively. The inhibitory effect of the three agents on collagenase gene expression was partially reversed by exogenous PGE 2 , which confirms that major histocompatibility complex class II-induced collagenase gene expression is regulated through a PGE 2 -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-β1) on a major histocompatibility complex class II-induced response and support the involvement of COX-2 and cPLA 2 in major histocompatibility complex class II-induced interstitial collagenase production in human fibroblast-like synoviocytes.