Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt

被引：347

作者：

Ichiyama, Kenji ^{[1
]}

Yoshida, Hideyuki ^{[1
]}

Wakabayashi, Yu ^{[2
]}

Chinen, Takatoshi ^{[1
]}

Saeki, Kazuko ^{[1
]}

Nakaya, Mako ^{[1
]}

Takaesu, Giichi ^{[1
]}

Hori, Shohei ^{[3
]}

Yoshimura, Akihiko ^{[1
,2
]}

Kobayashi, Takashi ^{[1
]}

机构：

[1] Kyushu Univ, Med Inst Bioregulat, Div Mol & Cellular Immunol, Higashi Ku, Fukuoka 8128582, Japan

[2] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan

[3] RIKEN Res Ctr Allergy & Immunol, Res Unit Immune Homeostasis, Tsurumi Ku, Kanagawa 2300045, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2008年 / 283卷 / 25期

关键词：

D O I：

10.1074/jbc.M801286200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：17003 / 17008

页数：6

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