Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction
Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction
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DOI：
10.1016/j.immuni.2008.07.018
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发表时间：
2008-10-17
期刊：
影响因子：
32.4
通讯作者：
Hirano, Toshio
中科院分区：
文献类型：
--
作者：
Ogura, Hideki;Murakami, Masaaki;Hirano, Toshio
失调的细胞因子表达和信号传导是许多自身免疫性疾病的主要贡献者。白细胞介素-17A（IL-17 A）和IL-6在许多以免疫自我识别为特征的疾病中是重要的，并且已知IL-6诱导T辅助17（Th 17）细胞的分化。在这里，我们描述了IL-17 A触发的IL-6信号传导的正反馈回路，其涉及成纤维细胞中转录因子核因子（NF）-κ B和信号转导和转录激活因子3（STAT 3）的激活。重要的是，由IL-6信号转导子gp 130的细胞因子信号转导抑制因子3（SOCS 3）依赖性负调控的破坏引起的该环的增强有助于关节炎的发展。由于这种机制也增强了野生型小鼠的实验性自身免疫性脑脊髓炎（EAE），因此它可能是其他Th 17细胞介导的自身免疫性疾病的一般病因学过程。
Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feed back loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappa B and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.