Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines

Arthritis Rheum. 1998 Oct;41(10):1748-59. doi: 10.1002/1529-0131(199810)41:10<1748::AID-ART7>3.0.CO;2-3.


Objective: To determine whether direct cell-cell contact with stimulated T lymphocytes (a) differentially modulates the production of interstitial collagenase (matrix metalloproteinase 1 [MMP-1]) and tissue inhibitor of metalloproteinases 1 (TIMP-1) on human synoviocytes and dermal fibroblasts, and (b) induces the production of prostaglandin E2 (PGE2); and to identify the membrane-associated factors on T cell surfaces involved in these mechanisms.

Methods: Dermal fibroblasts and fibroblast-like synovial cells (synoviocytes) were cultured with fixed T cells, isolated plasma membranes from T cells, interleukin-1beta (IL-1beta; 250 pg/ml), or transforming growth factor beta (TGFbeta; 5 ng/ml). Culture supernatants were assayed for the production of MMP-1, TIMP-1, and PGE2. The expression of MMP-1 and TIMP-1 messenger RNA was analyzed by Northern blot of total fibroblast RNA.

Results: Membranes of stimulated T cells, i.e., human peripheral blood T lymphocytes (PBTL) and the human T cell line HUT-78, induced the production of PGE2 and MMP-1 on both synoviocytes and dermal fibroblasts. TIMP-1 production was enhanced upon contact with PBTL stimulated for short periods of time (2-4 hours) but not for longer periods. Similar results were obtained with CD4+ and CD8+ synovial tissue T cell clones (TCCs), which induced the production of TIMP-1 by fibroblasts when stimulated for short (2-4 hours), but not long, periods of time. This time dependency was not observed with HUT-78 cells. The production of MMP-1 by fibroblasts and synoviocytes upon cellular contact with stimulated T cells was higher than that induced by an optimum concentration of IL-1beta, whereas the production of PGE2 was equivalent or slightly lower. Cell membrane-associated IL-1alpha and tumor necrosis factor a, but not CD69, CD40 ligand, or CD11b, were involved in the induction of MMP-1 and PGE2 production, as shown by blockade experiments using monoclonal antibodies and cytokine antagonists.

Conclusion: Synovial tissue TCCs and PBTL stimulated for long periods of time trigger the production of PGE2 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 synoviocyte functions directly (i.e., by contact activation) and indirectly (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 stimulated T cells, our results strongly suggest that contact of synovial cells with chronically stimulated T lymphocytes favors matrix catabolism. By analogy, this mechanism may trigger tissue destruction in vivo and, thus, may potentiate tissue destruction in chronic inflammatory diseases such as RA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibody Formation
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Surface / immunology
  • Cell Communication
  • Cell Line
  • Collagenases / analysis*
  • Collagenases / genetics
  • Collagenases / metabolism
  • Dinoprostone / metabolism
  • Fibroblasts / enzymology*
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Humans
  • Interleukin-1 / pharmacology
  • Lectins, C-Type
  • Lymphocyte Activation / physiology
  • Macrophage-1 Antigen / immunology
  • Matrix Metalloproteinase 1
  • RNA, Messenger / metabolism
  • Synovial Membrane / cytology*
  • Synovial Membrane / enzymology
  • Synovial Membrane / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Tissue Inhibitor of Metalloproteinase-1 / analysis*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta / pharmacology


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Surface
  • CD69 antigen
  • Interleukin-1
  • Lectins, C-Type
  • Macrophage-1 Antigen
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • Collagenases
  • Matrix Metalloproteinase 1
  • Dinoprostone