Immunology Group, Bioprocessing Technology Institute, Centros, Singapore.
J Immunol. 2010 Feb 15;184(4):1849-57. doi: 10.4049/jimmunol.0901509. Epub 2010 Jan 8.
The cytokines and transcription factors that promote Th17 cell development have been extensively studied. However, the signaling pathways that antagonize Th17 differentiation remain poorly characterized. In this study, we report that pharmacologic inhibition of MEK-ERK signaling enhances the in vitro differentiation of Th17 cells and increases their gene expression of il-17a, il-17f, il-21, il-22, and il-23r. IL-2, which suppresses Th17 differentiation via STAT5 activation, also acts through ERK signaling to inhibit Th17 generation. In turn, ERK signaling is found to potentiate the production of IL-2 and activate STAT5, suggesting the existence of an autoregulatory loop to constrain Th17 development. Finally, compared with the transfer of untreated Th17 cells, the transfer of ERK-inhibited Th17 cells leads to accelerated onset and exacerbated colitis in immunodeficient mice. Our data indicate that MEK-ERK signaling negatively regulates Th17 differentiation in a Th cell-intrinsic manner.
促进 Th17 细胞发育的细胞因子和转录因子已得到广泛研究。然而，拮抗 Th17 分化的信号通路仍未得到充分描述。在这项研究中，我们报告说，MEK-ERK 信号的药理学抑制增强了 Th17 细胞的体外分化，并增加了它们的 il-17a、il-17f、il-21、il-22 和 il-23r 的基因表达。通过 STAT5 激活抑制 Th17 分化的 IL-2 也通过 ERK 信号抑制 Th17 的产生。反过来，ERK 信号被发现可以增强 IL-2 的产生并激活 STAT5，这表明存在一个自调节回路来限制 Th17 的发育。最后，与未经处理的 Th17 细胞的转移相比，ERK 抑制的 Th17 细胞的转移导致免疫缺陷小鼠中结肠炎的发病加速和恶化。我们的数据表明，MEK-ERK 信号以 Th 细胞内在的方式负调节 Th17 分化。
