Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt
Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt
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DOI：
10.1074/jbc.m801286200
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发表时间：
2008-06-20
影响因子：
4.8
通讯作者：
Kobayashi, Takashi
中科院分区：
文献类型：
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作者：
Ichiyama, Kenji;Yoshida, Hideyuki;Kobayashi, Takashi
细胞因子转化生长因子-β 1（TGF-β 1）将初始T细胞转化为防止自身免疫的调节性T细胞。然而，在白细胞介素（IL）-6的存在下，还发现TGF-β 1促进分化为产生IL-17的辅助性T（Th 17）细胞，该辅助性T细胞深深参与自身免疫和炎症。然而，TGF-β 1和IL-6是如何决定这种不同的命运的还没有阐明。在这里，我们发现，一个主调节器的Th 17，视黄酸相关的孤儿受体γ t（ROR γ t），迅速诱导TGF-β 1，而不管IL-6的存在。IL-6降低Foxp 3表达，并且T细胞系中Foxp 3的过表达导致IL-17 A表达的强烈降低。我们已经表征了IL-17 A启动子，并发现ROR γ t结合足以激活HEK 293 T细胞中的最小启动子。ROR γ t介导的IL-17 A启动子激活被Foxp 3的强制表达抑制。Foxp 3通过Foxp 3的外显子2区直接与ROR γ t相互作用。Foxp 3的外显子2区域和叉头（FKH）结构域对于抑制ROR γ t介导的IL-17 A启动子激活是必需的。我们提出Foxp 3的诱导是抑制Th 17和极化成诱导型Treg的机制。
The cytokine, transforming growth factor-beta 1 (TGF-beta 1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta 1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-beta 1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gamma t (ROR gamma t), was rapidly induced by TGF-beta 1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that ROR gamma t binding is sufficient for activation of the minimum promoter in the HEK 293T cells. ROR gamma t-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with ROR gamma t through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of ROR gamma t-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.