Glycogen synthase kinase-3 controls IL-10 expression in CD4(+) effector T-cell subsets through epigenetic modification of the IL-10 promoter
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- BRISTOL UNIVERSITY
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.
|Number of pages||13|
|Journal||European Journal of Immunology|
|Publication status||Published - 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