Vitamin D receptor negatively regulates bacterial-stimulated NF-κB activity in intestine

Shaoping Wu, Anne P. Liao, Yinglin Xia, Yan Chun Li, Jian Dong Li, R. Balfour Sartor, Jun Sun

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)686-697
Number of pages12
JournalAmerican Journal of Pathology
Volume177
Issue number2
DOIs
StatePublished - Aug 2010
Externally publishedYes

Bibliographical note

Funding Information:
Supported by NIH grant DK075386 (J.S.) and the National Gnotobiotic Rodent Resource Center NIH grant USPHS 1 P40 RR018603-03 (R.B.S.) and P30 DK 34987.

Fingerprint

Dive into the research topics of 'Vitamin D receptor negatively regulates bacterial-stimulated NF-κB activity in intestine'. Together they form a unique fingerprint.

Cite this