c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells

J Leukoc Biol. 2010 Apr;87(4):703-12. doi: 10.1189/jlb.0909639. Epub 2009 Dec 30.

Abstract

Previous studies have shown that IL-6 potently induces IL-21 production in CD4(+) T cells, whereas TGF-beta inhibits IL-6-induced IL-21 production in CD4(+) T cells. In this study, we addressed the mechanisms underlying the transcriptional regulation of IL-21 production in CD4(+) T cells. We found that IL-6 induced c-Maf expression in CD4(+) T cells and that the enforced expression of c-Maf induced IL-21 production in CD4(+) T cells without IL-6, IL-4/STAT6 signaling, or an autocrine effect of IL-21. Moreover, we found that c-Maf directly bound to and activated IL-21P and the CNS-2 enhancer through MARE sites. On the other hand, we also found that although TGF-beta up-regulated IL-6-induced c-Maf expression in CD4(+) T cells, TGF-beta inhibited c-Maf-induced IL-21 production in CD4(+) T cells. Finally, we found that Foxp3 bound to IL-21P and the CNS-2 enhancer and inhibited c-Maf-induced IL-21 production modestly but significantly in CD4(+) T cells. Taken together, these results suggest that c-Maf induces IL-21 production directly in CD4(+) T cells by activating IL-21P and the CNS-2 enhancer and that TGF-beta suppresses c-Maf-induced IL-21 production in CD4(+) T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Enhancer Elements, Genetic / physiology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Interleukin-21
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / biosynthesis*
  • Interleukins / genetics
  • Interleukins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic / physiology*
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / immunology
  • Proto-Oncogene Proteins c-maf / metabolism*
  • STAT6 Transcription Factor
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*
  • Up-Regulation / immunology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-6
  • Interleukins
  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Transforming Growth Factor beta
  • Interleukin-4
  • Interleukin-21