Neutralizations of IL-17A and IL-21 regulate regulatory T cell/T-helper 17 imbalance via T-helper 17-associated signaling pathway in immune thrombocytopenia
Neutralizations of IL-17A and IL-21 regulate regulatory T cell/T-helper 17 imbalance via T-helper 17-associated signaling pathway in immune thrombocytopenia
复制标题
在免疫性血小板减少症中，IL-17A 和 IL-21 的中和通过 T 辅助细胞 17 相关信号通路调节调节性 T 细胞/T 辅助细胞 17 失衡
DOI：
10.1517/14728222.2015.1016499
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发表时间：
2015-06-01
影响因子：
5.8
通讯作者：
Hou, Ming
中科院分区：
文献类型：
--
作者：
Hu, Yu;Wang, Xiuwen;Hou, Ming
目的：调节性T细胞/辅助性T细胞17（Treg/Th 17）失衡是免疫性血小板减少症（ITP）发病的关键，IL-17 A和IL-21在ITP中过表达。IL-17 A和IL-21在Treg/Th 17失衡和ITP病理生理中的作用和机制尚不清楚。研究方法：用细胞因子或抗体处理ITP患者和健康对照的外周血单核细胞（PBMC）和CD 3 + T细胞以增加或中和IL-17 A或IL-21水平72 h。分析Treg/Th 17分化、凋亡、增殖和Th 17分化相关转录因子。结果：初诊ITP患者自然Treg/Th 17降低，缓解后恢复。IL-17 A或IL-21在体外可增加Th 17，降低TcR，下调Treg/Th 17。相反，IL-17 A或IL-21的中和作用降低了Th 17，增加了Tcl 3，并上调了Treg/Th 17。IL-17 A或IL-21的逆转作用由Th 17相关转录因子介导。IL-17 A或IL-21增强STAT-1、STAT-3、STAT-5或RAR相关孤儿受体C（RORC），而抗IL-17 A或抗IL-21 mAb下调ITP PBMC中STAT-1、STAT-5或RORC转录本。增殖无明显差异。IL-21抑制ITP PBMC的凋亡。结论：IL-17 A和IL-21在体外通过Th 17相关信号通路诱导ITP患者Th 17细胞分化，抑制Th 17细胞再分化。它突出了IL-17 A或IL-21阻断作为ITP的新治疗靶点的潜在价值。
Objective: The imbalance of regulatory T cell/T-helper 17 (Treg/Th17) is critical for the pathogenesis of immune thrombocytopenia (ITP) and IL-17A and IL-21 are overexpressed in ITP. The effects and mechanisms of IL-17A and IL-21 in Treg/Th17 imbalance and ITP pathophysiology are not clarified. Methods: Peripheral blood mononuclear cells (PBMCs) and CD3+ T cells from ITP patients and healthy controls were treated with cytokines or antibodies to increase or neutralize IL-17A or IL-21 levels for 72 h. Treg/Th17 differentiation, apoptosis, proliferation and Th17 differentiation-associated transcriptional factors were analyzed. Results: Natural Treg/Th17 decreased in newly diagnosed ITP patients and recovered after remission. IL-17A or IL-21 increased Th17, decreased Tregs and downregulated Treg/Th17 in vitro. Conversely, neutralization of IL-17A or IL-21 decreased Th17, increased Tregs and up-regulated Treg/Th17. The reverse effects of IL-17A or IL-21 were mediated by Th17-associated transcriptional factors. IL-17A or IL-21 enhanced STAT-1, STAT-3, STAT-5 or RAR-related orphan receptor C (RORC), whereas anti-IL-17A or anti-IL-21 mAb downregulated STAT-1, STAT-5 or RORC transcripts in ITP PBMCs. Proliferation showed no significant difference. IL-21 inhibited apoptosis in ITP PBMCs. Conclusion: IL-17A and IL-21 induce Th17 and inhibit Tregs re-differentiation via Th17-associated signaling pathway in ITP patients in vitro. It highlights the potential value of IL-17A or IL-21 blockade as a novel therapeutic target for ITP.