CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice.
CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice.
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DOI：
10.1016/j.bbrc.2013.04.096
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发表时间：
2013-06
影响因子：
3.1
通讯作者：
H. Yoshida;H. Kotani;T. Kondo;I. Tani;Xuetao Wei;Sanae Tsuruta;A. Kimura;M. Asakawa;Minako Ito;S. Nagai;A. Yoshimura
中科院分区：
文献类型：
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作者：
H. Yoshida;H. Kotani;T. Kondo;I. Tani;Xuetao Wei;Sanae Tsuruta;A. Kimura;M. Asakawa;Minako Ito;S. Nagai;A. Yoshimura
与自身免疫性疾病有关的Th 17细胞需要IL-6和TGF-β进行早期分化。包括JNK和RhoA-ROCK通路在内的多条Smad非依赖性通路参与了Th 17的主要调节因子RORγt的诱导，但Smad非依赖性通路的分子机制尚不清楚。为了确定参与Th 17分化的新途径，我们筛选了285种已知信号传导途径的化学抑制剂。其中，我们发现Kenpaullone，一种GSK 3-β和CDK抑制剂，有效抑制TGF-β介导的RORγt诱导，并增强原代T细胞中Foxp 3的诱导。另一种CDK抑制剂Roscovitine（而非其他GSK 3-β抑制剂）可抑制Th 17分化并增强iTreg发育。Kenpaullone和Roscovitine抑制实验性自身免疫性脑脊髓炎（EAE），一种典型的Th 17介导的自身免疫性疾病模型。这两种化合物在TGF-β存在下增强STAT 5磷酸化并恢复IL-2产生。这些数据表明，CDK抑制剂调节TGF-β信号传导途径，其恢复TGF-β介导的对IL-2产生的抑制，从而改变Th 17/iTreg平衡。
Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of RORγt, the master regulator of Th17, however, molecular mechanisms underlying Smad-independent pathway remain largely unknown. To identify novel pathways involved in Th17 differentiation, we screened 285 chemical inhibitors for known signaling pathways. Among them, we found that Kenpaullone, a GSK3-β and CDK inhibitor, efficiently suppressed TGF-β-mediated RORγt induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-β inhibitors, suppressed Th17 differentiation and enhanced iTreg development. Kenpaullone and Roscovitine suppressed experimental autoimmune encephalomyelitis (EAE), a typical Th17-mediated autoimmune disease model. These two compounds enhanced STAT5 phosphorylation and restored IL-2 production in the presence of TGF-β. These data suggest that CDK inhibitors modulate TGF-β-signaling pathways, which restore TGF-β-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance.