Ogura Hideki, Murakami Masaaki, Okuyama Yuko, Tsuruoka Mineko, Kitabayashi Chika, Kanamoto Minoru, Nishihara Mika, Iwakura Yoichiro, Hirano Toshio
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Immunity. 2008 Oct 17;29(4):628-36. doi: 10.1016/j.immuni.2008.07.018. Epub 2008 Oct 9.
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-feedback loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappaB 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.
细胞因子表达和信号传导失调是多种自身免疫性疾病的主要促成因素。白细胞介素-17A（IL-17A）和IL-6在许多以免疫自我识别为特征的疾病中起重要作用，并且已知IL-6可诱导辅助性T细胞17（Th17）细胞的分化。在此，我们描述了一种IL-17A触发的IL-6信号正反馈回路，该回路涉及成纤维细胞中转录因子核因子（NF）-κB和信号转导及转录激活因子3（STAT3）的激活。重要的是，细胞因子信号传导抑制因子3（SOCS3）对IL-6信号转导子gp130的依赖性负调节的破坏导致该回路增强，这促成了关节炎的发展。由于该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Th17细胞介导的自身免疫性疾病的一般病因过程。
