Glia. 2014 May;62(5):725-35. doi: 10.1002/glia.22637.
The family of interleukin 17 receptors (IL17Rs), subtypes IL17RA-IL17RE, is targeted by the group of pro-inflammatory IL17 cytokines (IL17A-F) and moreover the newly developed anti-IL17A antibody secukinumab (AIN457) has shown promise in Phase II trials in multiple sclerosis. Here, we show that human astrocytes, isolated from a fetal cerebral cortex, express IL17RA and IL17RC and in vitro treatment with IL17A increases protein levels of IL6 in human astrocytes, which is enhanced in the presence of TNFα, as determined by homogeneous time resolved fluorescence. Studies on acutely isolated mouse astrocytes are comparable to human astrocytes although the protein levels of IL6 are lower in mouse astrocytes, which also show a lower response to IL17F and IL1β in promoting IL6 levels. In human astrocytes, IL17A and TNFα also induce mRNA expression of IL6, IL8 and the Th17 cytokines CXCL1, CXCL2, and CCL20, with little effect on Th1 cytokines CXCL9, CXCL10, and CXCL11. The effects of IL17A are associated with nuclear translocation of the NF-κB transcription factor, as determined by immunocytochemistry, where treatment of human astrocytes with the inhibitors of the NF-κB pathway and with secukinumab inhibits the IL17A and IL17A/TNFα-induced increase in nuclear translocation of NF-κB and levels of IL6. Taken together the data shows that IL17A signaling plays a key role in regulating the levels of cytokines, such as IL6, in human astrocytes via a mechanism that involves NF-κB signaling and that selective inhibition of IL17A signaling attenuates levels of pro-inflammatory molecules in astrocytes.
白细胞介素 17 受体（IL17R）家族，包括亚型 IL17RA-IL17RE，是促炎白细胞介素 17 细胞因子（IL17A-F）的靶标，此外，新型抗白细胞介素 17A 抗体 secukinumab（AIN457）在多发性硬化症的 II 期临床试验中显示出前景。在这里，我们表明，从胎脑皮质分离的人星形胶质细胞表达 IL17RA 和 IL17RC，体外用 IL17A 处理可增加人星形胶质细胞中 IL6 的蛋白水平，而在 TNFα存在下，这一水平增强，如均相时间分辨荧光法所测定。急性分离的小鼠星形胶质细胞的研究与人类星形胶质细胞相似，尽管小鼠星形胶质细胞中 IL6 的蛋白水平较低，并且对 IL17F 和 IL1β在促进 IL6 水平方面的反应较低。在人星形胶质细胞中，IL17A 和 TNFα也诱导 IL6、IL8 和 Th17 细胞因子 CXCL1、CXCL2 和 CCL20 的 mRNA 表达，对 Th1 细胞因子 CXCL9、CXCL10 和 CXCL11 的影响较小。IL17A 的作用与 NF-κB 转录因子的核易位有关，如免疫细胞化学所测定，用 NF-κB 途径的抑制剂和 secukinumab 处理人星形胶质细胞可抑制 IL17A 和 IL17A/TNFα诱导的 NF-κB 核易位和 IL6 水平的增加。总之，数据表明，IL17A 信号通过涉及 NF-κB 信号的机制在调节人星形胶质细胞中细胞因子（如 IL6）的水平方面发挥关键作用，并且选择性抑制 IL17A 信号可降低星形胶质细胞中促炎分子的水平。
