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

Research output: Contribution to journalArticlepeer-review


  • Elaine V Hill
  • T H Sky Ng
  • Bronwen R Burton
  • Charly M Oakley
  • Karim Malik

Colleges, School and Institutes


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
Issue number4
Early online date27 Jan 2015
Publication statusPublished - Apr 2015


  • 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