IL-1R signaling promotes STAT3 and NF-B factor recruitment to distal cis-regulatory elements that regulate Il17a/f transcription

Abstract

Interleukin (IL)-1 plays a critical role in IL-6– and transforming growth factor (TGF)–initiated Th17 differentiation and induction of Th17-mediated autoimmunity. However, the means by which IL-1 regulates various aspects of Th17 development remain poorly understood. We recently reported that IL-1 enhances STAT3 phosphorylation via NF-B–mediated repression of SOCS3 to facilitate Il17 transcription and Th17 differentiation, identifying an effect of IL-1 signaling on proximal events of STAT3 signaling. Here, we show that IL-1 promotes STAT3 binding to key cis-elements that control IL-17 expression. Additionally, we demonstrate that the IL-1–induced NF-B factor RelA directly regulates the Il17a/f loci in cooperation with STAT3. Our findings reveal that IL-1 impacts both proximal signaling events and downstream interactions between transcription factors and cis-regulatory elements to promote Il17a/f transcription and Th17 differentiation.