Zhang Yuan, Huang Rongrong, Zhang Yanhong, Yi Hongwei, Bai Ying, Chao Jie, Yao Honghong
Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Inflammopharmacology. 2016 Feb;24(1):33-42. doi: 10.1007/s10787-015-0256-x. Epub 2016 Jan 19.
Our previous study demonstrated IL-17-mediated induction of MIP-1α through its binding to the cognate IL-17RA and MIP-1α was involved in astrocyte activation. Transient receptor potential canonical (TRPC) channel was involved in astrocyte activation, however, whether TRPC channel regulates MIP-1α expression in the context of multiple sclerosis (MS) remains largely unknown. In this study we identify the essential role of TRPC channel in IL-17-mediated MIP-1α expression and astrocyte activation. Moreover, treatment of astrocytes with IL-17 activated MAPKs and PI3K/Akt signaling pathways with downstream NF-κB pathways. Interestingly, the TRPC blocker-SKF96365 (10 μM) and Norgestimate (10 μM) significantly inhibited the increased expression of MIP-1α via suppression of IL-17-mediated ERK, p38 and JNK MAPKs and PI3K/Akt pathway activation, thereby underscoring the role of TRPC channel in this process. Together these data underpin the role of TRPC channel as a novel target that regulates MIP-1α expression and cell activation-mediated by IL-17 with implications for therapeutic intervention for reversal of neuroinflammation inflicted by IL-17. Understanding the regulation of MIP-1α expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with MS.
我们之前的研究表明，白细胞介素-17（IL-17）通过与同源白细胞介素-17受体A（IL-17RA）结合介导巨噬细胞炎性蛋白-1α（MIP-1α）的诱导，且MIP-1α参与星形胶质细胞活化。瞬时受体电位阳离子通道亚家族C成员（TRPC）通道参与星形胶质细胞活化，然而，在多发性硬化症（MS）背景下TRPC通道是否调节MIP-1α表达仍 largely未知。在本研究中，我们确定了TRPC通道在IL-17介导的MIP-1α表达和星形胶质细胞活化中的重要作用。此外，用IL-17处理星形胶质细胞可激活丝裂原活化蛋白激酶（MAPKs）和磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/Akt）信号通路以及下游核因子κB（NF-κB）通路。有趣的是，TRPC阻断剂——SKF96365（10 μM）和去氧孕烯（10 μM）通过抑制IL-17介导的细胞外信号调节激酶（ERK）、p38和应激活化蛋白激酶（JNK） MAPKs以及PI3K/Akt通路激活，显著抑制了MIP-1α表达的增加，从而强调了TRPC通道在此过程中的作用。这些数据共同支持了TRPC通道作为一个新靶点的作用，该靶点调节由IL-17介导的MIP-1α表达和细胞活化，对逆转IL-17所致神经炎症的治疗干预具有重要意义。了解MIP-1α表达的调节可能为与MS相关的神经炎症潜在治疗靶点的开发提供见解。
