Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis
Weicheng Liu, … , Stephen B. Hanauer, Yan Chun Li
Weicheng Liu, … , Stephen B. Hanauer, Yan Chun Li
Published August 15, 2013
Citation Information: J Clin Invest. 2013;123(9):3983-3996. https://doi.org/10.1172/JCI65842.
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Research Article Gastroenterology

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

Abstract

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+CD45RBhi 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.

Authors

Weicheng Liu, Yunzi Chen, Maya Aharoni Golan, Maria L. Annunziata, Jie Du, Urszula Dougherty, Juan Kong, Mark Musch, Yong Huang, Joel Pekow, Changqing Zheng, Marc Bissonnette, Stephen B. Hanauer, Yan Chun Li

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Figure 1

Reduced VDR expression in patients with IBD.

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Reduced VDR expression in patients with IBD. (A) Representative H&E ...
(A) Representative H&E histology of colonic biopsies obtained from normal subjects and CD and UC patients. Original magnification, ×100. (B) Representative immunostaining of colonic biopsies from normal control and CD and UC patients with anti-VDR antibodies. Arrows indicate VDR staining in the epithelial cells. Original magnification, ×100. (C) Microarray heatmap showing relative VDR transcript levels in normal and UC colonic biopsies. Red color indicates high transcript levels, and green color represents low levels. n ≥10 in each group. (D–F) Representative Western blots of colonic biopsies from the Chicago cohort (D) and the Shenyang cohort (E) with anti-VDR antibodies and respective densitometric quantitation (F) of VDR protein levels in each cohort (Full, uncut gels are shown in the supplemental material. Supplemental material available online with this article; doi: 10.1172/JCI65842DS1). §P < 0.001 versus normal (n = 5–12). Patients are numbered in the Shenyang cohort. ac, active; qu, quiescent; D, diseased lesion tissues; N, normal tissue. (G) Serum 25-hydroxyvitamin D concentrations in normal controls and IBD patients from the Chicago and Shenyang cohorts as indicated. Average values are marked by horizontal lines.