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

J Biol Chem. 2008 Jun 20;283(25):17003-8. doi: 10.1074/jbc.M801286200. Epub 2008 Apr 23.

Abstract

The cytokine, transforming growth factor-beta1 (TGF-beta1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta1 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-beta1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gammat (RORgammat), was rapidly induced by TGF-beta1 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 RORgammat binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORgammat-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORgammat through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORgammat-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Interleukin-17 / chemistry*
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptors, Retinoic Acid / chemistry*
  • Receptors, Thyroid Hormone / chemistry*
  • Sequence Homology, Nucleic Acid
  • T-Lymphocytes / metabolism
  • Transcription, Genetic*

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Rorc protein, mouse