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J. Biol. Chem., Vol. 283, Issue 22, 14955-14962, May 30, 2008

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F1000 Biology *Recommended* - FREE!

STAT6 Inhibits TGF-β1-mediated Foxp3 Induction through Direct Binding to the Foxp3 Promoter, Which Is Reverted by Retinoic Acid Receptor^*

Hiromi Takaki, Kenji Ichiyama, Keiko Koga, Takatoshi Chinen, Giichi Takaesu, Yuki Sugiyama, Shigeaki Kato^¶, Akihiko Yoshimura¹, and Takashi Kobayashi²

From the Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, and ^¶Insitute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1 Bunkyo-ku, Tokyo 113-0032, Japan

It has been shown that transforming growth factor β1 (TGF-β1) is critical in the generation of CD4⁺CD25⁺Foxp3⁺-inducible regulatory T cells (iTregs) from naïve CD4⁺T cells. However, in contrast to natural Tregs, TGF-β1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-β1-induced Foxp3 levels were maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-β1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-β1. Retinoic acid in the presence of TGF-β1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.

Received for publication, February 12, 2008 , and in revised form, March 28, 2008.

^* This work was supported by special grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, the Takeda Science Foundation, the Clinical Research Foundation, the Kato Memorial Foundation, Suzuken Memorial Foundation, the Naito Foundation, the Nakatomi Foundation, the Yakuruto Bioscience Foundation, Japan Intractable Disease Research Foundation, the Mitsubishi Pharama Research Foundation, and the Princess Takamatsu Cancer Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence may be addressed. Tel.: 81-92-642-6822; Fax: 81-92-642-6825; E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp. ² To whom correspondence may be addressed. E-mail: takashik{at}bioreg.kyushu-u.ac.jp.

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