Department of Medicine, Columbia University, New York, New York, USA.
J Clin Invest. 2010 Sep;120(9):3280-95. doi: 10.1172/JCI42856. Epub 2010 Aug 9.
Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.
IL-17 和 IL-21 的失调产生在许多自身免疫性疾病中起着关键的致病作用。因此，阐明自身免疫性疾病中 IL-17 和 IL-21 不适当合成的机制，可以为这些疾病的潜在治疗方法提供重要的见解。在这里，我们已经表明，丝氨酸-苏氨酸激酶 Rho 相关卷曲螺旋蛋白激酶 2（ROCK2）在 Th17 偏斜条件下在小鼠 T 细胞中被激活，并磷酸化干扰素调节因子 4（IRF4），IRF4 是产生 IL-17 和 IL-21 的必需转录因子。我们还证明了 ROCK2 介导的 IRF4 磷酸化调节了 IL-17 和 IL-21 的合成和 Th17 细胞的分化。虽然 WT 小鼠的 CD4+T 细胞在 Th17 条件下生理性地激活 ROCK2，但自发自身免疫的 2 种不同小鼠模型中的 CD4+T 细胞在中性条件下异常激活 ROCK2。此外，ROCK 抑制剂的给药改善了这些自身免疫性小鼠中观察到的 IL-17 和 IL-21 的失调产生以及炎症和自身抗体反应。因此，我们的发现揭示了 ROCK2、IRF4 和 IL-17 和 IL-21 的产生之间的关键联系，并支持了选择性抑制 ROCK2 可能是治疗自身免疫性疾病的重要治疗方案的观点。
