Stat6 and c-Jun Mediate Th2 Cell-Specific IL-24 Gene Expression

Abstract

TCR signaling regulates multiple aspects of T cell function by controlling expression of various cytokine genes. IL-24 is a multifunctional cytokine belonging to the IL-10 family. It displays anticancer effects in diverse cancer cells and regulates immunopathology of psoriasis and rheumatoid arthritis. IL-24 also plays an important role in B cell differentiation. Mouse IL-24 gene is selectively expressed in activated Th2 cells upon TCR stimulation. However, the molecular mechanisms by which TCR stimulation induces IL-24 gene expression are still unclear. In this study, to elucidate the mechanism of Th2 cell-specific expression of IL-24, we identified a proximal promoter region (−157/+95bp) that plays critical role in activating the IL-24 gene in Th2 cells. This region has a Th2 cell-specific open chromatin structure along with permissive histone modifications. In vivo binding of Stat6 and AP-1 (c-Jun) to the IL-24 promoter locus in Th2 cells synergistically transactivated the IL-24 promoter. Stat6 and c-Jun proteins were found to physically cooperate with each other and upregulated IL-24 gene transcription. Knockdown of either Stat6 or c-Jun suppressed endogenous IL-24 gene expression in Th2 cells. In summary, TCR stimulation induces IL-24 expression in Th2 cells by the coordinate action of Stat6 and c-Jun transcription factors at the transcriptional level.

IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

“…A recent report indicated that IL-24 expression is Th2 specific, mediated in part by STAT6 function through the IL-24 promoter [67]. We asked whether there might be functional elements dispersed throughout this locus, as found for the IL4/IL13/IL5 locus; these can be identified through genomic analysis, especially when multiple datasets are combined [4,68].…”

The IL-20 subfamily of cytokines — from host defence to tissue homeostasis

“…In addition, the proximal promoter of IL24 contains binding sites for STAT6 and JUN, and these transcription factors are thought to function synergistically to regulate IL-24 production by T H 2 cells 63 . Production of IL-24 by group 2 ILCs has not yet been reported.…”

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

“…ϩ T cells were cultured in vitro under Th1, Th2, and Th9 differentiation conditions by following the previously reported studies (6,51). Expression level of IL-9 was measured among the various in vitro differentiated T helper subsets.…”

“…In general, enrichment of acetyl histone H3 (AcH3), acetyl histone H4 (AcH4) and histone H3 lysine 4 dimethylation (H3K4Me2) to promoters correlates well with their transcriptionally active status (30,50,51). Thus, to further confirm the differential chromatin structure of the IL-9 promoter between WT and NFAT1 Ϫ/Ϫ Th9 cells, relative amounts of recruited AcH3, AcH4, and H3K4Me2 levels were analyzed by a ChIP assay.…”