Lack of Vitamin D Receptor Leads to Hyperfunction of Claudin-2 in Intestinal Inflammatory Responses.

Abstract:

Background:Vitamin D3 and vitamin D receptor (VDR) are involved in the pathogenesis of inflammatory bowel disease (IBD) and bacterial infection. Claudin-2 is a junction protein that mediates paracellular water transport in epithelia. Elevation of Claudin-2 is associated with active IBD. However, VDR involved in epithelial junctions under inflammation and infection remains largely unknown. We investigated the mechanisms on how VDR and Claudin-2 are related in inflamed states. Methods:Using cultured VDR-/- enteroids, human intestinal epithelial cells, VDR-/- mice with Salmonella- or DSS-colitis, and human IBD samples, we investigated the mechanisms how VDR and Claudin-2 are related in inflamed states. Results:After Salmonella infection had taken place, we observed significantly enhanced Claudin-2 and an increased bacterial invasion and translocation. A lack of VDR regulation led to a robust increase of Claudin-2 at the mRNA and protein levels post-infection. In DSS-treated VDR-/- mice, Claudin-2 was significantly increased. Location and quantification of Claudin-2 protein in the mouse colons treated with DSS also confirmed these results. Inflammatory cytokines were significantly higher in the serum and mRNA levels in intestine, which are known to increase Claudin-2. Furthermore, in inflamed intestine of ulcerative colitis patients, VDR expression was low and Claudin-2 was enhanced. Mechanistically, we identified the enhanced Claudin-2 promoter activity through the binding sites of NF-κB and STAT in inflamed VDR-/- cells. Conclusions:Our studies have identified a new role for intestinal epithelial VDR in regulating barrier functions in the context of infection and inflammation.

journal_name

Inflamm Bowel Dis

authors

Zhang YG,Lu R,Xia Y,Zhou D,Petrof E,Claud EC,Sun J

doi

10.1093/ibd/izy292

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

97-110

issue

1

eissn

1078-0998

issn

1536-4844

pii

5115658

journal_volume

25

pub_type

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