Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Nature Immunology (Impact Factor: 24.97). 03/2011; 12(3):247-54. DOI: 10.1038/ni.1995
Source: PubMed

ABSTRACT Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

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Available from: Kiyoshi Hirahara, Jul 28, 2015
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    • "Consistently, we saw significant overlaps between the genes affected by each perturbation and known targets of key TFs both in Th17 cells (e.g., BATF and IRF4) and in other CD4 + T cells (e.g., STAT4, GATA3, and Foxp3; Table S1; this analysis was based on publically available data of TF-target interactions; see Supplemental Experimental Procedures). Overall, these results suggest a mode of competition or balance modulated by the transcriptional activity of RORgt (Bettelli et al., 2006; Yang et al., 2011; Zhou et al., 2008). "
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    • "array [126] H3K4me1, H3K4me3, H3K27ac, CTCF IL4 ChIP-seq + RNA-seq [75] p300 (WT, Stat6−/−, Gata3 oe; Stat6−/− and Gata3 oe); H3K4me1 (WT and Stat6−/−) IL4 ChIP-seq + RNA-seq [79] Th17 GATA3 TGFb + IL6 + IL1b ChIP-seq + RNA-seq [80] H3K4me3, H3K27me3 TGFb + IL6 + IL1b ChIP-seq + RNA-seq [76] STAT3, STAT5 TGFb + IL6 ChIP-seq + Exp. array [128] pSTAT3; H3K4me3 (WT and Stat3−/−) TGFb + IL6 ChIP-seq + Exp. array [78] "
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