Contribution of hypoxia-inducible factor to intestinal epithelial IFNγ signaling 3796

Abstract Description IFN?? contributes fundamentally to intestinal mucosal homeostasis. High levels of IFNγ provide antimicrobial defense, repress intestinal stem cell proliferation, decrease barrier integrity, and recruit T cells to inflamed areas. In response to IFNγ, intestinal epithelial cells (IECs) upregulate MHC I and II, assuming an “immune-like” phenotype. IECs play important roles in innate and adaptive immunity. Notably, IECs exist in a unique environment of low oxygen levels, termed “physiological hypoxia”, at baseline. The transcription factor hypoxia-inducible factor (HIF) mediates global hypoxia responses and is stabilized in the IECs in health and during inflammation. Moreover, it has been established that IFN?? represses the HIF1β subunit, but the role of HIF in modulating epithelial IFNγ responses is unknown. Our lab has identified hypoxia-mediated modulation of IEC IFNγ response genes. Therefore, we hypothesize that HIF controls IEC responses to IFNγ and modulates IFNγ signaling. Through evaluation of IECs in vitro, we have identified HIF-dependent decreases in IFNγ-induced MHC II expression and associated transcriptional regulation of CIITA by HIF. In parallel, we have identified HIF-dependent increases in STAT1 expression, part of canonical IFNγ signaling, suggesting that HIF stabilization inhibits STAT1 signaling. Together, these results reveal a HIF-IFNγ signaling axis that may be fundamental to mucosal immune responses in the intestine. Funding Sources Supported by NIH/NIDDK DK50189 and T32GM149361. Topic Categories Mucosal and Regional Immunology (MUC)