Glycogen synthase kinase-3 controls IL-10 expression in CD4(+) effector T-cell subsets through epigenetic modification of the IL-10 promoter

Elaine V Hill, T H Sky Ng, Bronwen R Burton, Charly M Oakley, Karim Malik, David Wraith

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)
31 Downloads (Pure)

Abstract

The serine/threonine kinase glycogen synthase kinase-3 (GSK3) plays an important role in balancing pro- and anti-inflammatory cytokines. We have examined the role of GSK3 in production of IL-10 by subsets of CD4(+) T helper cells. Treatment of naive murine CD4(+) T cells with GSK3 inhibitors did not affect their production of IL-10. However, treatment of Th1 and Th2 cells with GSK3 inhibitors dramatically increased production of IL-10. GSK3 inhibition also led to upregulation of IL-10 among Th1, Th2, and Th17 subsets isolated from human blood. The encephalitogenic potential of GSK3 inhibitor treated murine Th1 cells was significantly reduced in adoptive transfer experiments by an IL-10-dependent mechanism. Analysis of the murine IL-10 promoter in response to inhibition of GSK3 in Th1 cells showed modification to a transcriptionally active state indicated by changes in histone H3 acetylation and methylation. Additionally, GSK3 inhibition increased expression of the transcription factors c-Maf, Nfil3, and GATA3, correlating with the increase in IL-10. These findings are important in the context of autoimmune disease since they show that it is possible to reprogram disease-causing cells through GSK3 inhibition.

Original languageEnglish
Pages (from-to)1103-1115
Number of pages13
JournalEuropean Journal of Immunology
Volume45
Issue number4
Early online date27 Jan 2015
DOIs
Publication statusPublished - Apr 2015

Keywords

  • Acetylation
  • Adoptive Transfer
  • Animals
  • Basic-Leucine Zipper Transcription Factors
  • Cells, Cultured
  • Dendritic Cells
  • Encephalomyelitis, Autoimmune, Experimental
  • GATA3 Transcription Factor
  • Glycogen Synthase Kinase 3
  • Histones
  • Humans
  • Inflammation
  • Interleukin-10
  • Methylation
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-maf
  • Th1 Cells
  • Th17 Cells
  • Th2 Cells
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • CD4+
  • T cells
  • Epigenetic
  • IL-10

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