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.

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。