Upregulation of Synoviocyte COX-2 Through Interactions with T Lymphocytes: Role of Interleukin 17 and Tumor Necrosis Factor-a

LISA K. STAMP, LESLIE G. CLELAND, and MICHAEL J. JAMES

ABSTRACT.

Objective. T lymphocytes infiltrating rheumatoid synovium may alter the function of resident synoviocytes. We investigated the influence on synoviocyte cyclooxygenase-2 (COX-2) expression and prostaglandin E₂ (PGE₂) production exerted by soluble factors released by T cells, with particular reference to interleukin 17 (IL-17).

Methods. Human peripheral blood T cells were stimulated with antibodies directed against CD3 and CD28. Harvested T cell supernatants were applied to cultured human fibroblast-like synoviocytes in culture. The effects of IL-17 alone and in combination with tumor necrosis factor-a (TNF-a) were examined using recombinant cytokines and neutralizing antibodies. Synoviocyte COX-2 expression and PGE₂ production were examined.

Results. Supernatants from stimulated T cells upregulated COX-2 expression and increased PGE₂ production by synoviocytes. The T cell supernatants were found to contain IL-17 and TNF-a. Recombinant IL-17 upregulated synoviocyte COX-2 expression and enhanced TNF-a stimulated synoviocyte COX-2 expression. The upregulation of synoviocyte COX-2 expression by supernatants from stimulated T cells was partially inhibited by addition of neutralizing antibodies against IL-17 or TNF-a or by treatment of T cells with cyclosporin A prior to stimulation.

Conclusion. Activated T cells are capable of paracrine upregulation of synoviocyte COX-2 expression and PGE₂ production through release of soluble mediators. T cell derived IL-17, especially in combination with TNF-a, may contribute to ongoing inflammation through its effects on COX-2 expression and PGE₂ production. These data provide additional evidence for the contribution of T cells in rheumatoid inflammation and highlight the potential of IL-17 as a therapeutic target. (J Rheumatol 2004;31:1246-54)

Key Indexing Terms:

SYNOVIOCYTES
T LYMPHOCYTES
EICOSANOIDS
CYCLOOXYGENASE

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From the Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia.

Supported by grants from The National Health and Medical Research Council of Australia.

L.K. Stamp, FRACP; L.G. Cleland, MD, FRACP; M.J. James, PhD.

Address reprint requests to Dr. M.J. James, Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia. E-mail: michael.james@adelaide.edu.au

Submitted May 9, 2003; revision accepted December 30, 2003.

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