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

研究成果: Article

125 引用 (Scopus)

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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.

元の言語English
ページ(範囲)14955-14962
ページ数8
ジャーナルJournal of Biological Chemistry
283
発行部数22
DOI
出版物ステータスPublished - 2008 5 30

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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