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

Kenji Ichiyama, Hideyuki Yoshida, Yu Wakabayashi, Takatoshi Chinen, Kazuko Saeki, Mako Nakaya, Giichi Takaesu, Shohei Hori, Akihiko Yoshimura, Takashi Kobayashi

Research output: Contribution to journalArticle

310 Citations (Scopus)

Abstract

The cytokine, transforming growth factor-β1 (TGF-β1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-β1 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-β1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor γt (RORγt), was rapidly induced by TGF-β1 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 RORγt binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORγt-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORγt through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORγt-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.

Original languageEnglish
Pages (from-to)17003-17008
Number of pages6
JournalJournal of Biological Chemistry
Volume283
Issue number25
DOIs
Publication statusPublished - 2008 Jun 20

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Interleukin-17
Transcription
Transforming Growth Factors
T-cells
Interleukin-6
Messenger RNA
Chemical activation
Autoimmunity
Exons
T-Lymphocytes
Th17 Cells
HEK293 Cells
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Tretinoin
Polarization
Cytokines
Inflammation
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., ... Kobayashi, T. (2008). Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. Journal of Biological Chemistry, 283(25), 17003-17008. https://doi.org/10.1074/jbc.M801286200

Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. / Ichiyama, Kenji; Yoshida, Hideyuki; Wakabayashi, Yu; Chinen, Takatoshi; Saeki, Kazuko; Nakaya, Mako; Takaesu, Giichi; Hori, Shohei; Yoshimura, Akihiko; Kobayashi, Takashi.

In: Journal of Biological Chemistry, Vol. 283, No. 25, 20.06.2008, p. 17003-17008.

Research output: Contribution to journalArticle

Ichiyama, K, Yoshida, H, Wakabayashi, Y, Chinen, T, Saeki, K, Nakaya, M, Takaesu, G, Hori, S, Yoshimura, A & Kobayashi, T 2008, 'Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt', Journal of Biological Chemistry, vol. 283, no. 25, pp. 17003-17008. https://doi.org/10.1074/jbc.M801286200
Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M et al. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. Journal of Biological Chemistry. 2008 Jun 20;283(25):17003-17008. https://doi.org/10.1074/jbc.M801286200
Ichiyama, Kenji ; Yoshida, Hideyuki ; Wakabayashi, Yu ; Chinen, Takatoshi ; Saeki, Kazuko ; Nakaya, Mako ; Takaesu, Giichi ; Hori, Shohei ; Yoshimura, Akihiko ; Kobayashi, Takashi. / Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 25. pp. 17003-17008.
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