Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 4, Pages 1103-1115Publisher
WILEY
DOI: 10.1002/eji.201444661
Keywords
CD4(+) Tcells; Epigenetic; Glycogen synthase kinase-3; IL-10
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Funding
- Wellcome Trust [091074]
- MRC Developmental Pathway Funding Scheme (DPFS) grant
- MRC [MR/K007645/1] Funding Source: UKRI
- Medical Research Council [MR/K007645/1] Funding Source: researchfish
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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(+) Tcells 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.
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