IRF4 regulates IL-10 gene expression in CD4(+) T cells through differential nuclear translocation

Cell Immunol. 2011;268(2):97-104. doi: 10.1016/j.cellimm.2011.02.008. Epub 2011 Mar 4.

Abstract

CD4(+) T cells play critical roles in the generation of protective immunity against a variety of pathogens. The main two types of effector CD4(+) T cells, Th1 and Th2 are characterized by their ability to produce signature cytokines. Among them, IL-10 is a multi-functional cytokine that plays a crucial role in maintaining the balance between immunity and tolerance. Although IL-10 is produced by both differentiated primary Th1 and Th2 cells, Th2 cells produce much higher levels of IL-10 upon stimulation. However, little information is available on the molecular mechanisms of IL-10 gene regulation at the transcriptional level. Interferon regulatory factor IRF4 is a member of the IRF family of transcription factors and plays critical roles in the development of CD4(+) T cells into Th2 cells. In this present study, we elucidate the underlying mechanism of IRF4 mediated IL-10 gene transcription in primary CD4(+) T cells. Th2 specific binding of IRF4 to the IRF4 responsive elements in IL-10 locus potentiated IL-10 expression in Th2 cells. Knockdown of IRF4 by siRNA decreased IL-10 expression level in Th2 cells. Nuclear translocation of IRF4 was much higher in Th2 cells upon stimulation, which contribute to maintain IL-10(high) phenotype of Th2 cells. Collectively, our results suggest that stimulation driven quantitative differences of IRF4 in the nucleus and its binding to IL-10 regulatory elements are crucial mechanisms to induce IL-10(high) gene expression in Th2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Cell Nucleus / physiology*
  • Flow Cytometry
  • Gene Expression Regulation / immunology*
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / immunology
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA / chemistry
  • RNA / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Specific Pathogen-Free Organisms
  • Th2 Cells / immunology
  • Th2 Cells / physiology*
  • Transcription, Genetic

Substances

  • IL10 protein, mouse
  • Interferon Regulatory Factors
  • RNA, Small Interfering
  • interferon regulatory factor-4
  • Interleukin-10
  • RNA