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.
Subject(s)
Glycogen Synthase Kinase 3/metabolism , Interleukin-10/biosynthesis , Th1 Cells/immunology , Th17 Cells/immunology , Th2 Cells/immunology , Acetylation , Adoptive Transfer , Animals , Basic-Leucine Zipper Transcription Factors/biosynthesis , Cells, Cultured , Dendritic Cells/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , GATA3 Transcription Factor/biosynthesis , Glycogen Synthase Kinase 3/antagonists & inhibitors , Histones/metabolism , Humans , Inflammation/immunology , Interleukin-10/genetics , Methylation , Mice , Mice, Knockout , Promoter Regions, Genetic , Proto-Oncogene Proteins c-maf/biosynthesis , Th1 Cells/transplantationABSTRACT
Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4(+) T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3(+) and FoxP3(-) T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically.
