Department of Immunobiology, Jinan University, Guangzhou, China.
J Biol Regul Homeost Agents. 2013 Jan-Mar;27(1):79-93.
Notch signaling plays an important role in differentiation of T cells. However, little is known as to action of it in differentiation of Th17 cell subset. In this study, a soluble Jagged-1/Fc chimera protein (Jagged-1) was directly used to activate Jagged-1-Notch signaling, while Hes-1-targeting siRNA was used to knock down Hes-1 gene to investigate effect of Jagged-1-Hes-1 signaling on the differentiation of CD4+ T cells into Th17 cells. The results showed that Jagged-1 could promote the expression of Hes-1 and Deltex-1 mRNAs and the expression of NICD, Hes-1 and Deltex-1 proteins, which might be significantly blocked by DAPT, a specific inhibitor of Notch signaling. Jagged-1-Hes-1 signaling resulted in the markedly decreased in situ expression of RORgammat in the CD4+ T cells induced by IL-6 plus TGF-ß. Flow cytometric analysis showed the reduction of IL-17 production in CD4+ T cells by Jagged-1, but the enhancement of it by Hes-1-targeting siRNA. The level of IL-10 produced by the treated cells was also enhanced, whereas the expression of IL-17 was prominently attenuated, which could be offset by anti-Jagged-1 antibody or DAPT. The results indicate that Jagged-1-Hes-1 signaling can suppress the skewing of CD4+ T cells toward Th17 cells via RORgammat, for which Hes-1 may be crucial.
Notch 信号通路在 T 细胞分化中发挥重要作用。然而， Notch 信号通路在 Th17 细胞亚群分化中的作用知之甚少。在这项研究中，我们直接使用可溶性 Jagged-1/Fc 嵌合体蛋白（Jagged-1）来激活 Jagged-1-Notch 信号通路，同时使用 Hes-1 靶向 siRNA 敲低 Hes-1 基因，以研究 Jagged-1-Hes-1 信号通路对 CD4+T 细胞向 Th17 细胞分化的影响。结果表明，Jagged-1 可促进 Hes-1 和 Deltex-1mRNA 的表达以及 NICD、Hes-1 和 Deltex-1 蛋白的表达，这些表达可被 Notch 信号通路的特异性抑制剂 DAPT 显著阻断。Jagged-1-Hes-1 信号通路导致 IL-6 加 TGF-β诱导的 CD4+T 细胞中 RORgammat 的原位表达明显减少。流式细胞术分析表明，Jagged-1 减少了 CD4+T 细胞中 IL-17 的产生，但 Hes-1 靶向 siRNA 增强了其产生。处理后的细胞产生的 IL-10 水平也增加，而 IL-17 的表达明显减弱，这种减弱可以被抗 Jagged-1 抗体或 DAPT 抵消。这些结果表明，Jagged-1-Hes-1 信号通路可以通过 RORgammat 抑制 CD4+T 细胞向 Th17 细胞的偏斜，其中 Hes-1 可能是关键的。
