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

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.

Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy

“…However, recently, alterations of histone H3 acetylation and methylation at the IL-10 promotor region following in vitro IL-10 induction have been reported although the relevance for phenotype stabilization is not clear. 41,42 Taken together, regulation of IL-10 production might rather reflect a dynamic, self-limiting state of inflammatory and Treg differentiation modulated on demand by external signals. However, the molecular regulation and stability of IL-10 production by the various T-cell subsets requires more detailed analyses.…”

c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes

“…c-Maf is phosphorylated by the Ser/Thr glycogen synthase kinase 3β (GSK3) in human multiple myeloma cell lines and in the lens, leading to protein stabilization (54,55). However, whether GSK3 exerts a similar role in T cells is difficult to evaluate as GSK3 inhibition increases expression of c-Maf in this context (56).…”

Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation

“…50). These include cell migration (51), CD4 + T cell differentiation to the Th17 (35,52) and Th1 (53) lineages, control of IL-10 production by CD4 + effector T cells (54,55), as well as CD8 + memory T cell development (56,57).…”