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

J Sun, J Kong, Y Duan, FL Szeto… - American Journal …, 2006 - journals.physiology.org
J Sun, J Kong, Y Duan, FL Szeto, A Liao, JL Madara, YC Li
American Journal of Physiology-Endocrinology and Metabolism, 2006journals.physiology.org
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-κB activation, a pathway
essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from
VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased
compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in …
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-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα 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-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β 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-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α 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-κB activation.
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