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Increased NF-B activity in fibroblasts lacking the vitamin D receptor

¹Department of Pathology, ²Department of Medicine, and ³Committee on Molecular Metabolism and Nutrition, Biological Science Division, The University of Chicago, Chicago, Illinois

Submitted 28 November 2005 ; accepted in final form 23 February 2006

1,25-Dihydroxyvitamin D [1,25(OH)₂D₃] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-B activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR^–/– mice, the basal level of B inhibitor (IB) protein was markedly decreased compared with VDR^+/– MEFs; however, degradation of IB and its phosphorylation in response to TNF- treatment or Salmonella infection were not altered in VDR^–/– cells, neither were the levels of IB kinase- and IB kinase- proteins. Consistent with IB reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR^–/– cells. In addition, 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 nuclear p65 DNA binding and NF-B transcriptional activity; consistently, induction of IL-6 by TNF- or IL-1 was much more robust in VDR^–/– than in VDR^+/– cells, indicating that VDR^–/– cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-B activity. The reduction of IB in VDR^–/– MEFs may be partially explained by the lack of VDR-mediated stabilization of IB by 1,25(OH)₂D₃. This is supported by the observation that IB degradation induced by TNF- was inhibited by 1,25(OH)₂D₃ in VDR^+/– cells, but not in VDR^–/– cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-B activation.

inflammation; nuclear factor-B; mouse embryonic fibroblasts

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