IMBALANCE BETWEEN INTERSTITIAL COLLAGENASE AND TISSUE INHIBITOR OF METALLOPROTEINASES-1 IN SYNOVIOCYTES AND FIBROBLASTS UPON DIRECT-CONTACTWITH STIMULATED T-LYMPHOCYTES - INVOLVEMENT OF MEMBRANE-ASSOCIATED CYTOKINES

Objective. To determine whether direct cell-cell contact,vith stimulat ed T lymphocytes (a) differentially modulates the production of inters titial collagenase (matrix metalloproteinase 1 [MMP-1]) and tissue inh ibitor of metalloproteinases 1 (TIMP-1) on human synoviocytes and derm al fibroblasts, and (b) induces the production of prostaglandin E-2 (P GE(2)); and to identify the membrane-associated factors on T cell surf aces involved in these mechanisms. Methods. Dermal fibroblasts and fib roblast-like synovial cells (synoviocytes) were cultured with fixed T cells, isolated plasma membranes from T cells, interleukin-1 beta (IL- 1 beta; 250 pg/ml), or transforming growth factor beta (TGF beta; 5 ng /ml), Culture supernatants,were assayed for the production of MMP-1, T IMP-1, and PGE(2), The expression of MMP-1 and TIMP-1 messenger RNA wa s analyzed by Northern blot of total fibroblast RNA, Results, Membrane s of stimulated T cells, i.e., human peripheral blood T lymphocytes (P BTL) and the human T cell line HUT-78, induced the production of PGE, and MMP-1 on both synoviocytes and dermal fibroblasts, TIMP-1 producti on was enhanced upon contact with PBTL stimulated for short periods of time (2-4 hours) but not for longer periods. Similar results were obt ained vith CD4+ and CD8+ synovial tissue T cell clones (TCCs), which i nduced the production of TIMP-1 by fibroblasts when stimulated for sho rt (2-4 hours), but not long, periods of time. This time dependency wa s not observed with HUT-78 cells. The production of MMP-1 by fibroblas ts and synoviocytes upon cellular contact with stimulated T cells was higher than that induced by an optimum concentration of IL-1 beta, whe reas the production of PGE(2) was equivalent or slightly lower. Cell m embrane-associated IL-la and tumor necrosis factor cu, but not CD69, C D40 ligand, or CD11b, were involved in the induction of MMP-1 and PGE( 2) production, as shown by blockade experiments using monoclonal antib odies and cytokine antagonists. Conclusion. Synovial tissue TCCs and P BTL stimulated for long periods of time trigger the production of PGE( 2) and MMP-1, but not TIMP-1, in synoviocytes and dermal fibroblasts, thus inducing an imbalance between the metalloenzyme and its inhibitor . These results demonstrate that T cells may affect fibroblast and syn oviocyte functions directly (i.e., by contact activation) and indirect ly (i.e., by activation of cytokine production in monocyte/macrophages , which in turn, trigger stromal cell functions). Since the production of MMPs in monocyte/macrophages is also induced upon contact with sti mulated T cells, our results strongly suggest that contact of synovial cells with chronically stimulated T lymphocytes favors matrix catabol ism. By analogy, this mechanism may trigger tissue destruction in vivo and, thus, may potentiate tissue destruction in chronic inflammatory diseases such as RA.