title: Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts.
abstract: We have used mouse embryonic fibroblasts (MEFs) derived from VDR(+/-) and VDR(-/-) mice to determine whether the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation. We found that the basal IkappaBalpha protein level was markedly decreased in VDR(-/-) MEFs compared to VDR(+/-) MEFs; however, degradation of IkappaBalpha and its phosphorylation were not altered in VDR(-/-) cells, neither were the levels of IKKalpha and IKKbeta proteins. Consistently, p65 nuclear translocation was increased in unstimulated VDR(-/-) cells. The physical interaction between VDR and p65 was absent in VDR(-/-) MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in NF-kappaB transcriptional activity. Consistently, induction of IL-6 by TNFalpha or IL-1beta was much more robust in VDR(-/-) than in VDR(+/-) cells, indicating that VDR(-/-) cells are more susceptible to inflammatory stimulation. Therefore, fibroblasts lacking VDR appear to be more pro-inflammatory due to the intrinsic high NF-kappaB activity. The reduction of IkappaBalpha in VDR(-/-) MEFs may be partially explained by the lack of VDR-mediated stabilization of IkappaBalpha by 1,25(OH)(2)D(3). These data suggest that VDR plays an inhibitory role in the regulation of NF-kappaB activation.
authors.affiliation: Committee on Molecular Metabolism and Nutrition, Biological Science Division, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Frances L
authors.initials: FL
authors.lastname: Szeto
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Yingli
authors.initials: Y
authors.lastname: Duan
authors.forename: Anne
authors.initials: A
authors.lastname: Liao
authors.forename: James L
authors.initials: JL
authors.lastname: Madara
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D018167:Receptors, Calcitriol