期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 9, 页码 3983-3996出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65842
关键词
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资金
- NIH [HL085793, 5P30CA014599-36, NIDDK P30DK42086]
- Gastrointestinal Research Foundation (GIRF) Associate Board
- Foundation for Clinical Research in Inflammatory Bowel Disease (FCRIBD)
- International Organization for the Study of Inflammatory-Bowel Disease (IOIBD)
- Liaoning Government (China)
- CTSA grant from the National Center for Research Resources (NCRR) [UL1 RR024999]
- Kohut fund
- Goldgraber fellowship
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-kappa B 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.
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