Protein Kinase CK2 Maintains Reciprocal Balance Between Th17 and Treg Cells in the Pathogenesis of UC
Protein Kinase CK2 Maintains Reciprocal Balance Between Th17 and Treg Cells in the Pathogenesis of UC
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蛋白激酶 CK2 在 UC 发病机制中维持 Th17 和 Treg 细胞之间的相互平衡
DOI：
10.1093/ibd/izab312
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发表时间：
2021-12-14
影响因子：
4.9
通讯作者：
Zhou, Guangxi
中科院分区：
文献类型：
--
作者：
Dong, Guanjun;Yang, Yonghong;Zhou, Guangxi
背景辅助性T细胞17和调节性T细胞的平衡在溃疡性结肠炎（UC）的发生发展中起着至关重要的作用。蛋白激酶CK 2参与免疫相关疾病的发病机制，但目前尚未发现如何打破这种平衡。然而，其对UC发展的影响尚不清楚。方法采用实时荧光定量聚合酶链反应（qRT-PCR）和免疫组化方法检测UC患者结肠组织中CK 2的表达。分别用CK 2抑制剂CX4945和Csnk 2干扰慢病毒转染外周血CD 4 + T细胞，采用qRT-PCR、酶联免疫吸附试验和流式细胞术检测细胞因子mRNA和蛋白水平的变化。此外，将CX 4945给予三硝基苯磺酸（TNBS）诱导的结肠炎小鼠模型，以确定CK 2对肠道炎症的调节功能。结果溃疡性结肠炎患者炎症黏膜中CK 2水平明显升高，并在CD 4 + T细胞中呈高表达。CX4945阻断CK 2可抑制Th 17，但可促进UC患者CD 4 + T细胞中的调节性T细胞（Treg）免疫应答。此外，CK 2阻断减轻TNBS诱导的小鼠结肠炎。抑制CK 2可抑制Th 17，但通过降低信号转导和转录激活因子（STAT）3的磷酸化水平和增加STAT 5的磷酸化水平促进Treg分化。RNA-Seq和免疫共沉淀分析进一步表明，CK 2可以与SIRT 1相互作用，下调SIRT 1的表达，SIRT 1参与Th 17抑制，但促进Treg分化。Sirtuin 1上调可改善TNBS诱导的结肠炎，而SIRT 1阻断可加重小鼠TNBS诱导的结肠炎。结论CK 2通过维持Th 17和Treg细胞的相互平衡，在UC的发生发展中起重要作用。阻断蛋白激酶CK 2可能成为治疗UC的新途径。
Background T helper 17 and regulatory T cells balance have crucial effects on the development of ulcerative colitis (UC). Currently, how to break this balance has not yet been found. Protein kinase CK2 is involved in the pathogenesis of immune-related disorders. However, its effects on the development of UC are obscure. Methods The level of CK2 in the colonic tissues of UC patients was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and immune-histochemistry. Peripheral blood CD4+ T cells were treated with CK2 inhibitor CX4945 or transfected with Csnk2-interfering lentivirus; the mRNA expression and protein levels of inflammatory cytokines were detected by qRT-PCR, enzyme-linked immunosorbent assay, and flow cytometry. Moreover, CX4945 was administered to trinitrobenzene sulfonic acid (TNBS)-induced colitis mice model for determining the function of CK2 on the regulation of intestinal inflammation. Results The CK2 level was markedly increased in inflamed mucosa of UC and highly expressed in CD4+ T cells. Blockade of CK2 by CX4945 inhibited Th17 but promoted regulatory T-cell (Treg) immune responses in CD4+ T cells from patients with UC. Moreover, CK2 blockade alleviated TNBS-induced colitis in mice. Inhibition of CK2 suppressed Th17 but promoted Treg differentiation by decreasing the phosphorylation level of signal transducer and activator of transcription (STAT) 3 and increasing the phosphorylation level of STAT5. The RNA-Seq and co-immunoprecipitation analysis further showed that CK2 could interact with Sirtuin 1 (SIRT1) and downregulate SIRT1 expression, which participated in Th17 inhibition but promoted Treg differentiation. Sirtuin 1 upregulation ameliorated TNBS-induced colitis, whereas SIRT1 blockade aggravated TNBS-induced colitis in mice. Conclusions CK2 have crucial effects on the development of UC by maintaining reciprocal balance between Th17 and Treg cells. Protein kinase CK2 blockade might be considered as a new therapeutic approach for UC treatment.