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IL-10 is a pleiotropic cytokine with multifaceted functions in establishing immune homeostasis. Although expressed by Th1 and Th2 cells, conventional Th1 cells produce marginal levels of IL-10 compared with their Th2 counterparts. In this study, we investigated the epigenetic mechanisms of Il-10 gene expression in Th1 cells. Bioinformatics EMBOSS CpG plot analysis and bisulfite pyrosequencing revealed three CpG DNA methylation sites in the Il-10 gene locus. Progressive DNA methylation at all of the CpG regions of interest (ROIs) established a repressive program of Il-10 gene expression in Th1 cells. Interestingly, Th1 cells treated with IL-12 and IL-27 cytokines, thereby mimicking a chronic inflammatory condition in vivo, displayed a significant increase in IL-10 production that was accompanied by selective DNA demethylation at ROI 3 located in intron 3. IL-10-producing T cells isolated from lymphocytic choriomeningitis virus-infected mice also showed enhanced DNA demethylation at ROI 3. Binding of STAT1 and STAT3 to demethylated ROI 3 enhanced IL-10 expression in an IL-12/IL-27-dependent manner. Accordingly, CD4+ T cells isolated from STAT1- or STAT3-knockout mice were significantly defective in IL-10 production. Our data suggest that, although stably maintained DNA methylation at the promoter may repress IL-10 expression in Th1 cells, locusspecific reversible DNA demethylation may serve as a threshold platform to control transient Il-10 gene expression. [ABSTRACT FROM AUTHOR]