Upregulation of synoviocyte COX-2 through interactions with T lymphocytes: role of interleukin 17 and tumor necrosis factor-alpha.
Upregulation of synoviocyte COX-2 through interactions with T lymphocytes: role of interleukin 17 and tumor necrosis factor-alpha.
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发表时间：
2004-07
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通讯作者：
L. Stamp;L. Cleland;M. James
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作者：
L. Stamp;L. Cleland;M. James
目的：T淋巴细胞浸润类风湿滑膜可改变滑膜细胞功能。我们研究了T细胞释放的可溶性因子对滑膜细胞环氧化酶-2 （COX-2）表达和前列腺素E2 （PGE2）产生的影响，特别是白细胞介素17 （IL-17）。方法用CD3和CD28抗体刺激人外周血T细胞。将收集的T细胞上清液应用于培养的人成纤维细胞样滑膜细胞。利用重组细胞因子和中和抗体检测IL-17单独和联合肿瘤坏死因子-a （TNF-a）的作用。检测滑膜细胞COX-2的表达和PGE2的产生。结果受刺激T细胞的上清液上调COX-2的表达，增加滑膜细胞的PGE2生成。发现T细胞上清液含有IL-17和TNF-a。重组IL-17上调滑膜细胞COX-2表达，增强TNF-a刺激的滑膜细胞COX-2表达。刺激T细胞的上清液对滑膜细胞COX-2表达的上调可以通过添加抗IL-17或TNF-a的中和抗体或在刺激前用环孢素A处理T细胞来部分抑制。结论活化的T细胞能够通过释放可溶性介质上调滑膜细胞COX-2的表达和PGE2的产生。T细胞来源的IL-17，特别是与TNF-a结合，可能通过其对COX-2表达和PGE2产生的影响而促进持续的炎症。这些数据为T细胞在类风湿炎症中的作用提供了额外的证据，并强调了IL-17作为治疗靶点的潜力。
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.