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 Yoshimura, Takashi Kobayashi

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14955-14962
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number22
DOIs
Publication statusPublished - 2008 May 30

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Retinoic Acid Receptors
Transforming Growth Factors
Interleukin-4
T-cells
Regulatory T-Lymphocytes
Tretinoin
Binding Sites
Allergies
T-Lymphocytes
Acetylation
Gene Deletion
Histones
Chromatin
Hypersensitivity
Genes
Chemical activation
Antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

STAT6 inhibits TGF-β1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. / Takaki, Hiromi; Ichiyama, Kenji; Koga, Keiko; Chinen, Takatoshi; Takaesu, Giichi; Sugiyama, Yuki; Kato, Shigeaki; Yoshimura, Akihiko; Kobayashi, Takashi.

In: Journal of Biological Chemistry, Vol. 283, No. 22, 30.05.2008, p. 14955-14962.

Research output: Contribution to journalArticle

Takaki, Hiromi ; Ichiyama, Kenji ; Koga, Keiko ; Chinen, Takatoshi ; Takaesu, Giichi ; Sugiyama, Yuki ; Kato, Shigeaki ; Yoshimura, Akihiko ; Kobayashi, Takashi. / STAT6 inhibits TGF-β1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 22. pp. 14955-14962.
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