Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.
Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.
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糖原合酶激酶 3 通过促进白细胞介素 9 的产生来促进 17 型 T 辅助细胞分化。
DOI：
10.1111/imm.13199
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发表时间：
2020
期刊：
影响因子：
6.4
通讯作者：
Beurel,Eléonore
中科院分区：
文献类型：
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作者：
Han,Dongmei;Medina-Rodriguez,EvaM;Lowell,JeffreyA;Beurel,Eléonore
辅助性T - 17 （Th17）细胞被认为是几种神经和精神疾病的有害影响的重要贡献者。因此，阐明控制Th17细胞产生的机制可能为开发针对广泛疾病的新干预措施提供新的策略。糖原合成酶激酶- 3 （GSK3）促进Th17细胞分化，但其机制才刚刚开始被理解。使用T细胞选择性缺失GSK3β和多种选择性药理GSK3抑制剂，我们发现GSK3抑制在体外Th17细胞分化2天后降低了C‐C基序趋化因子（ccl）20、C‐C基序趋化因子受体（ccr）6、白细胞介素（IL） 9、Runt相关转录因子（Runx）1、干扰素调节因子（Irf）4和C‐mafmRNA的表达。研究发现，这些作用不依赖于主调控转录因子视黄酸受体相关孤儿受体γ t (RORγT)，因为GSK3抑制仍然会降低RORγT缺失细胞中Th17细胞的分化。由于IL - 9在GSK3β−/−CD4细胞中下调约9倍，我们测试了在Th17细胞分化期间重新引入IL - 9是否会消除GSK3缺乏对Th17细胞分化的抑制。我们发现IL - 9过表达足以逆转GSK3抑制或缺失对Th17细胞分化的抑制。我们发现IL‐9部分通过信号转导和转录激活因子3 （STAT3）的激活来促进Th17细胞分化，并且IL‐9还可以增强STAT3与IL‐17启动子的结合。总之，这些发现表明IL - 9可能是GSK3β依赖性Th17细胞分化增强的重要介质。
T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase‐3 (GSK3), but the mechanisms for this are only beginning to be understood. Using T‐cell‐selective depletion of GSK3βand multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreasedC‐C motif chemokine(ccl)20,C‐C motif chemokine receptor (ccr)6,interleukin (IL)‐9,Runt‐related transcription factor (Runx)1,interferon regulatory factor (Irf)4andc‐mafmRNA expression after 2 days of Th17 cell differentiationin vitro. These effects were found to be independent of the master regulator transcription factor retinoic acid receptor‐related orphan receptorγT (RORγT), as GSK3 inhibition still reduced Th17 cell differentiation in RORγT‐depleted cells. Because IL‐9 was approximately ninefold down‐regulated in GSK3β−/−CD4 cells, we tested if reintroduction of IL‐9 during Th17 cell differentiation abolished the inhibition by GSK3 deficiency of Th17 cell differentiation. We found that IL‐9 over‐expression was sufficient to reverse the inhibition of Th17 cell differentiation by GSK3 inhibition or depletion. We found that IL‐9 enhances Th17 cell differentiation in part through signal transducer and activator of transcription 3 (STAT3) activation, and IL‐9 also enhances STAT3 binding to theIL‐17apromoter. Altogether, these findings suggest that IL‐9 might be an important mediator of GSK3β‐dependent enhancement of Th17 cell differentiation.