Vitamin D Receptor Negatively Regulates Bacterial-Stimulated NF-κB Activity in Intestine

• DOI: 10.2353/ajpath.2010.090998
• Publication Date: 2010-06-22T02:30:21Z
• Authors: Shaoping Wu; Anne P. Liao; Yinglin Xia; Yan Chun Li; Jian-Dong Li; R. Balfour Sartor; Jun Sun
• Keywords: Mice, Knockout; 0301 basic medicine; Salmonella Infections, Animal; 0303 health sciences; NF-kappa B; Vitamins; Cell Line; 3. Good health; Intestines; Mice; 03 medical and health sciences; Calcitriol; Salmonella; Animals; Humans; Receptors, Calcitriol; Intestinal Mucosa

Vitamin D receptor (VDR) plays an essential role in gastrointestinal inflammation. Most investigations have focused on the immune response; however, how bacteria regulate VDR and how VDR modulates the nuclear factor (NF)-κB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-κB activation in intestinal epithelia and the role of enteric bacteria on VDR expression. We found that VDR−/− mice exhibited a pro-inflammatory bias. After Salmonella infection, VDR−/− mice had increased bacterial burden and mortality. Serum interleukin-6 in noninfected VDR+/+ mice was undetectable, but was easily detectable in VDR−/− mice. NF-κB p65 formed a complex with VDR in noninfected wild-type mouse intestine. In contrast, deletion of VDR abolished VDR/P65 binding. P65 nuclear translocation occurred in colonic epithelial cells of untreated VDR−/− mice. VDR deletion also elevated NF-κB activity in intestinal epithelia. VDR was localized to the surface epithelia of germ-free mice, but to crypt epithelial cells in conventionalized mice. VDR expression, distribution, transcriptional activity, and target genes were regulated by Salmonella stimulation, independent of 1,25-dihydroxyvitamin D3. Our study demonstrates that commensal and pathogenic bacteria directly regulate colonic epithelial VDR expression and location in vivo. VDR negatively regulates bacterial-induced intestinal NF-κB activation and attenuates response to infection. Therefore, VDR is an important contributor to intestinal homeostasis and host protection from bacterial invasion and infection.