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

Sun, Jun, Juan Kong, Yingli Duan, Frances L. Szeto, Anne Liao, James L. Madara, and Yan Chun Li. Increased NFB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab 291: E315–E322, 2006. First published February 28, 2006; doi:10.1152/ajpendo.00590.2005.—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 NFB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR / mice, the basal level of B inhibitor (I B) protein was markedly decreased compared with VDR / MEFs; however, degradation of I B and its phosphorylation in response to TNFtreatment or Salmonella infection were not altered in VDR / cells, neither were the levels of I B kinaseand I B kinaseproteins. Consistent with I B 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 NFB transcriptional activity; consistently, induction of IL-6 by TNFor 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 NFB activity. The reduction of I B in VDR / MEFs may be partially explained by the lack of VDR-mediated stabilization of I B by 1,25(OH)2D3. This is supported by the observation that I B degradation induced by TNFwas 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 NFB activation.