蛋白激酶CK2调控Th17和Treg分化参与类风湿关节炎发病的研究

Rheumatoid arthritis (RA) is one of the severe disabling diseases; the abnormality of CD4+ T cells proliferation and differentiation is crucial in the pathogenesis of RA. It was found that the gene of CK2 was elevated in CD4+ T cells of RA patients and CK2 subunit kinase activity were induced upon CD4+ T cell activation in our preliminary experiment. Therefore, in this study, CD4+T cells of RA patientis and CIA modal will be activated and polirazated, and the role of CK2 in CD4+ T cells differentiation in vitro and the signaling pathway in the process will be identified. Furthermore, we will test the feasibility of targeting CK2 for RA therapy in vivo. This study will not only provide experimental basis for the role of CK2 in RA pathogenesis, but also provide new strategy for the specific therapy in RA.

类风湿关节炎（RA）是临床主要致残性疾病。CD4+T细胞增殖和分化异常是RA发病的中心环节。前期研究中我们发现RA患者外周血CD4+T细胞蛋白激酶CK2基因表达明显增高，且CD4+体外活化后CK2亚单位活性升高。在此基础上，本项目利用RA患者外周血和胶原诱导性关节炎（CIA)小鼠模型，率先研究CK2对CD4+T细胞各亚群体外分化的影响及其可能作用的信号通路；并进一步利用CIA动物模型探寻CK2抑制剂治疗CIA小鼠的可行性。本课题不仅为CK2在RA发病中的意义提供实验依据，而且为RA治疗提供新的思路。

我们前期的研究表明，CK2参与CD4+T细胞增殖和活化。本项目中我们研究了CK2参与类风湿关节炎（RA）发病的机制。用不同剂量的CK2抑制剂CX4945治疗RA患者的外周血和滑液单核细胞（PBMC和SFMC）以及胶原诱导的关节炎（CIA）小鼠的脾细胞后分析Th1、Th2、Th17和Treg细胞水平。评估CIA小鼠经口灌胃给予CX4945后关节炎评分、骨破坏、组织损伤和CD4+T细胞亚群的变化情况。结果证明，CX4945治疗可显著抑制RA患者PBMC、SFMC和CIA小鼠脾细胞的Th1和Th17细胞分化，同时促进Th2细胞分化，抑制IFN-γ和IL-17A的产生。此外，CX4945可改善CIA小鼠关节炎的严重程度，同时降低Th1和Th17细胞。然而，CX4945对RA Treg细胞的影响似乎很小。这项研究表明，CK2是RA发病过程中Th1和Th17细胞分化的重要调节因子，可导致疾病加重。抑制CK2可能是治疗RA的有效途径。