Department of Clinical Immunology and Rheumatology, Immunogenomics and Infl ammation Research Unit, Hopital Edouard Herriot, University of Lyon, Lyon, France.
Ann Rheum Dis. 2012 May;71(5):768-76. doi: 10.1136/annrheumdis-2011-200468. Epub 2012 Jan 18.
Cardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor α (TNFα) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction.
Primary human EC were treated with IL-17 alone or combined with TNFα. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion.
IL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFα. IL-17 plus TNFα induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL-6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFα. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state.
These results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.
心血管事件仍是类风湿关节炎（RA）患者的主要死亡原因。为了研究细胞因子在这些观察结果中的作用，评估了肿瘤坏死因子α（TNFα）和白介素（IL）-17（RA 中的经典和新关键因子）对血管内皮细胞（EC）功能障碍的影响。
用 IL-17 单独或与 TNFα 联合处理原代人 EC。通过 qRT-PCR 和 Affymetrix 微阵列定量 mRNA 表达。使用血小板聚集、EC 迁移和侵袭的功能测定研究 IL-17 的作用。
IL-17 单独诱导了 248 个促炎基因，与 TNFα 联合诱导了 9803 个基因。IL-17 加 TNFα 协同诱导趋化因子基因，如 CCL5、IL-8 和细胞因子基因，如 IL-6。相反，IL-17 减少了参与炎症调节的基因，如 IL-33。IL-17 与 TNFα 协同诱导 EC 迁移和侵袭。用抗 CXCR4 抗体抑制这种侵袭，表明基质细胞衍生因子-1/C-X-C 趋化因子受体 4 轴的贡献。经 IL-17 处理的 EC 的上清液可诱导强烈的血小板聚集。IL-17 抑制内皮细胞 CD39/ATPDase 表达，后者是血小板激活的抑制剂。最后，IL-17 增强了组织因子等关键凝血基因，并降低了血栓调节蛋白，导致促血栓形成状态。
这些结果表明，IL-17 特别是与 TNFα 联合具有对血管的主要促凝和促血栓形成作用。
