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Am J Physiol Endocrinol Metab (February 28, 2006). doi:10.1152/ajpendo.00590.2005
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Submitted on November 29, 2005
Accepted on February 23, 2006

Increased NF-{kappa}B Activity in Fibroblasts Lacking the Vitamin D Receptor

Jun Sun1, Juan Kong2, Yingli Duan1, Frances L Szeto3, Anne Liao1, James L Madara1, and Yan Chun Li4*

1 Department of Pathology, University of Chicago, Chicago, IL, USA
2 Department of Medicine, University of Chicago, Chicago, IL, USA
3 Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL, USA
4 Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: cyan{at}medicine.bsd.uchicago.edu.

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-{kappa}B activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR(-/-) mice, the basal level of I{kappa}B{alpha} protein was markedly decreased compared to VDR(+/-) MEFs; however, degradation of I{kappa}B{alpha} and its phosphorylation in response to TNF{alpha} treatment or Salmonella infection were not altered in VDR(-/-) cells, neither were the levels of IKK{alpha} and IKK{beta} proteins. Consistent with I{kappa}B{alpha} 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-{kappa}B transcriptional activity; consistently, induction of IL-6 by TNF{alpha} or IL-1{beta} 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 pro-inflammatory due to the intrinsic high NF-{kappa}B activity. The reduction of I{kappa}B{alpha} in VDR(-/-) MEFs may be partially explained by the lack of VDR-mediated stabilization of I{kappa}B{alpha} by 1,25(OH)2D3. This is supported by the observation that I{kappa}B{alpha} degradation induced by TNF{alpha} 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-{kappa}B activation.




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