Upregulation of synoviocyte COX-2 through interactions with T lymphocytes: role of interleukin 17 and tumor necrosis factor-alpha.
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.


CONCLUSIONS
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.
Stamp
Lisa K
LK
Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia.
Cleland
Leslie G
LG
James
Michael J
MJ
D018929:Cell Culture Techniques; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators; D007375:Interleukin-1 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000276:immunology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D018836:Inflammation Mediators; D007375:Interleukin-1; D020381:Interleukin-17; D007527:Isoenzymes; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone