Vitamin D receptor negatively regulates bacterial-stimulated NF-kappaB activity in intestine.
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)-kappaB pathway in intestinal epithelial cells remain unexplored. This study investigated the effects of VDR ablation on NF-kappaB 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-kappaB 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-kappaB 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-kappaB activation and attenuates response to infection. Therefore, VDR is an important contributor to intestinal homeostasis and host protection from bacterial invasion and infection.
Wu
Shaoping
S
Gastroenterology & Hepatology Division, Department of Medicine, University of Rochester, Rochester, New York, USA.
Liao
Anne P
AP
Xia
Yinglin
Y
Li
Yan Chun
YC
Li
Jian-Dong
JD
Sartor
R Balfour
RB
Sun
Jun
J
D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000033:anatomy & histology / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D012475:Salmonella; D012481:Salmonella Infections, Animal / Q000378:metabolism; D014815:Vitamins / Q000378:metabolism
D016328:NF-kappa B; D018167:Receptors, Calcitriol; D014815:Vitamins; D002117:Calcitriol