Intestinal Epithelial Vitamin D Receptor Expression in IBD Patients and in Experimental Colitis

Vitamin D-deficiency is very prevalent in inflammatory bowel diseases. Global vitamin D receptor (VDR) deletion exaggerates colitis in mice, but the anti-colitic roles of immune and intestinal epithelial VDR are unclear. Here we report that epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis, and VDR up-regulation in intestinal epithelial cells (IECs) prevented mice from developing colitis. In both 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) colitis models, transgenic mice expressing human (h)VDR in the IECs were highly resistant to colitis, manifested by a marked reduction in clinical colitis scores and colonic histological damage compared to wild-type mice. Furthermore, reconstitution of the IECs with the hVDR transgene completely rescued VDR-null mice from severe colitis and death in both colitis models. Mechanistically, hVDR overexpression attenuated TNBS- or DSS-induced IEC apoptosis via blocking the induction of PUMA, a key pro-apoptotic regulator, and vitamin D down-regulates PUMA by blocking NF-κB activation. These results indicate that epithelial VDR inhibits colitis by protecting the mucosal epithelial barrier. The observation that hVDR rescues VDR-null mice from colitis despite a VDR-null immune system demonstrates that the anti-colitic activity of epithelial VDR is independent of immune VDR signals.