Vitamin D/Vdr Signaling Inhibits Colitis By Suppressing Hif-1 Activation In Colonic Epithelial Cells

Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD), and hypoxia-inducible factor 1a (HIF-1a) activation is demonstrated to be closely associated with chemicalinduced colitis. However, the association between vitamin D/VDR signaling and HIF-1a on IBD development remains a mystery. Here, we showed that HIF-1a expression was largely increased in the colonic epithelial cells of diseased tissues from patients with ulcerative colitis (UC). Consistently, HIF-1a activation was also improved in colonic epithelial cells upon TNFa treatment in a NF-KB pathway-dependent manner. HIF-1a inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF1a overexpression in colonic epithelial cells via regulating NF-KB pathway, resulting in the inhibition of IFNc and IL-1b overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1a expression in colonic epithelial cells. NEW & NOTEWORTHY This study demonstrates vitamin D/VDR signaling inhibits colitis by suppressing HIF-1a activation in colonic epithelial cells. Since the effect of vitamin D/VDR signaling is only apparent on patients who seem to be vitamin D deficient, the benefits of vitamin D supplementation in patients who are not vitamin D deficient need to be proven.