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

Am J Pathol. 2010 Aug;177(2):686-97. doi: 10.2353/ajpath.2010.090998. Epub 2010 Jun 21.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcitriol / metabolism
  • Cell Line
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestines / anatomy & histology
  • Intestines / microbiology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Salmonella
  • Salmonella Infections, Animal / metabolism
  • Vitamins / metabolism


  • NF-kappa B
  • Receptors, Calcitriol
  • Vitamins
  • Calcitriol