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Down-regulation of A3AR signaling by IL-6-induced GRK2 activation contributes to Th17 cell differentiation
Experimental Cell Research ( IF 3.3 ) Pub Date : 2021-01-09 , DOI: 10.1016/j.yexcr.2021.112482
Shanshan Hu , Paipai Guo , Zhen Wang , Zhengwei Zhou , Rui Wang , Mei Zhang , Juan Tao , Yu Tai , Weijie Zhou , Wei Wei , Qingtong Wang

IL-6-triggered Th17 cell expansion is responsible for the pathogenesis of many immune diseases including rheumatoid arthritis (RA). Traditionally, IL-6 induces Th17 cell differentiation through JAK-STAT3 signaling. In the present work, PKA inhibition reduces in vitro induction of Th17 cells, while IL-6 stimulation of T cells facilitates the internalization of A3AR and increased cAMP production in a GRK2 dependent manner. Inhibition of GRK2 by paroxetine (PAR) or genetic depletion of GRK2 restored A3AR distribution and prevented Th17 cell differentiation. Furthermore, in vivo PAR treatment effectively reduced the splenic Th17 cell proportion in a rat model of collagen-induced arthritis (CIA) which was accompanied by a significant improvement in clinical manifestations. These results indicate that IL-6-induced Th17 cell differentiation not only occurs through JAK-STAT3-RORγt but is also mediated through GRK2-A3AR-cAMP-PKA-CREB/ICER-RORγt. This elucidates the significance of GRK2-controlled cAMP signaling in the differentiation of Th17 cells and its potential application in treating Th17-driven immune diseases such as RA.



中文翻译:

IL-6诱导的GRK2激活下调A 3 AR信号传导有助于Th17细胞分化

IL-6触发的Th17细胞膨胀是许多免疫疾病(包括类风湿关节炎(RA))的发病机制的原因。传统上,IL-6通过JAK-STAT3信号传导诱导Th17细胞分化。在目前的工作中,PKA抑制可减少Th17细胞的体外诱导,而T细胞的IL-6刺激则以GRK2依赖性方式促进A 3 AR的内在化和cAMP产生的增加。帕罗西汀(PAR)抑制GRK2或GRK2的遗传耗竭可恢复A 3 AR分布并阻止Th17细胞分化。此外,体内在胶原诱导的关节炎(CIA)的大鼠模型中,PAR治疗有效降低了脾脏Th17细胞的比例,并伴随着临床表现的显着改善。这些结果表明IL-6诱导的Th17细胞分化不仅通过JAK-STAT3-RORγt发生,而且还通过GRK2-A 3 AR-cAMP-PKA-CREB ​​/ICER-RORγt介导。这阐明了GRK2控制的cAMP信号在Th17细胞分化中的重要性及其在治疗Th17驱动的免疫疾病(如RA)中的潜在应用。

更新日期:2021-01-18
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