SUPERANTIGEN-INDUCED COLLAGENASE GENE-EXPRESSION IN HUMAN IFN-GAMMA-TREATED FIBROBLAST-LIKE SYNOVIOCYTES INVOLVES PROSTAGLANDIN E(2) - EVIDENCE FOR A ROLE OF CYCLOOXYGENASE-2 AND CYTOSOLIC PHOSPHOLIPASE A(2)

MHC class II molecules expressed in lymphoid and nonlymphoid cells act as signal-transducer molecules. We demonstrate that engagement of MHC class II molecules on human IFN-gamma-treated fibroblast-like synovio cytes by their natural ligand, the staphylococcal enterotoxin A (SEA), selectively induces the production of interstitial collagenase over t he expression of the tissue inhibitor of metalloproteinase (TIMP). Col lagenase gene expression required de novo protein synthesis and was ac companied by high levels of PGE(2) production, suggesting its implicat ion in this response. Two inhibitors that affect prostaglandin biosynt hesis, indomethacin an arachidonyl-trifluoromethyl-ketone, inhibited b oth PGE(2) production and collagenase gene expression. The addition of exogenous PGE(2) to inhibitor-treated cells partially restored the SE A-induced collagenase, indicating a role for PGE(2) in this response. As cyclooxygenases (COX-1 and -2), cytosolic phospholipase A(2) (cPLA( 2)), and secreted PLA(2) (sPLA(2)) are the enzymes potentially implica ted in prostaglandin synthesis, their involvement in SEA-induced colla genase was investigated. The mRNA levels of COX-2 and cPLA(2) rapidly increased following ligation of MHC class II molecules, while COX-1 an d sPLA(2) mRNA levels were unchanged and transiently depressed, respec tively. SEA-induced COX-2 mRNA was translated adequately to protein, w hereas cPLA(2) protein level was not enhanced, but rapidly phosphoryla ted, a process previously linked to the enzyme activation. In conclusi on, this work demonstrates a selective induction of collagenase gene e xpression over its natural inhibitor TIMP in human IFN-gamma-treated f ibroblast-like synoviocytes mediated, at least in part, by PGE(2), and provides evidence that signaling via MHC class II molecules induces t he production of PGE(2) through enhanced production of COX-2 and possi bly activation of the cPLA(2).