Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis.
The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4(+)CD45RB(hi) T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Weicheng
W
Liu
Yunzi
Y
Chen
Maya Aharoni
MA
Golan
Maria L
ML
Annunziata
Jie
J
Du
Urszula
U
Dougherty
Juan
J
Kong
Mark
M
Musch
Yong
Y
Huang
Joel
J
Pekow
Changqing
C
Zheng
Marc
M
Bissonnette
Stephen B
SB
Hanauer
Yan Chun
YC
Li
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D015533:Transcriptional Activation; D014302:Trinitrobenzenesulfonic Acid; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; C488588:PUMA protein, mouse; D018167:Receptors, Calcitriol; D025521:Tumor Suppressor Proteins; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate