Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.,Immunology

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Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.
Immunology ( IF 4.9 ) Pub Date : 2020-04-11 , DOI: 10.1111/imm.13199
Dongmei Han ₁ , Eva M Medina-Rodriguez ₁ , Jeffrey A Lowell ₁ , Eléonore Beurel _{1,

2}

Affiliation

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 GSK3β and multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreased C‐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)4 and c‐maf mRNA expression after 2 days of Th17 cell differentiation in vitro . These effects were found to be independent of the master regulator transcription factor retinoic acid receptor‐related orphan receptor γ T (RORγ T), as GSK3 inhibition still reduced Th17 cell differentiation in RORγ T‐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 the IL‐17a promoter. Altogether, these findings suggest that IL‐9 might be an important mediator of GSK3β‐dependent enhancement of Th17 cell differentiation.

中文翻译：

糖原合酶激酶 3 通过促进白细胞介素 9 的产生来促进 T 辅助细胞 17 型分化。

17 型 T 辅助 (Th17) 细胞被认为是导致多种神经和精神疾病有害影响的重要因素。因此，阐明控制 Th17 细胞产生的机制可能为在广泛的疾病中开发新的干预措施提供新的策略。Th17 细胞分化由糖原合酶激酶 3 (GSK3) 促进，但其机制才刚刚开始被了解。使用 GSK3 β 的T 细胞选择性消耗和多种选择性药理学 GSK3 抑制剂，我们发现 GSK3 抑制降低了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 ,体外Th17 细胞分化 2 天后Runt 相关转录因子 (Runx)1、干扰素调节因子 (Irf)4和c-maf mRNA 表达。发现这些效应独立于主调节转录因子视黄酸受体相关孤儿受体γ T (ROR γ T)，因为 GSK3 抑制仍会降低 ROR γ T 耗尽细胞中的Th17 细胞分化。因为 IL-9 在 GSK3 β ^{-/- 中}下调了大约九倍CD4 细胞，我们测试了在 Th17 细胞分化过程中重新引入 IL-9 是否消除了 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 抑制或消耗对 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) 激活增强 Th17 细胞分化，并且 IL-9 还增强 STAT3 与IL-17a启动子的结合。总之，这些发现表明 IL-9 可能是 GSK3 β依赖性增强 Th17 细胞分化的重要介质。

更新日期：2020-04-11

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