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Increased NF-ΚB activity in fibroblasts lacking the vitamin D receptor.
- Source :
- American Journal of Physiology: Endocrinology & Metabolism; Aug2006, Vol. 291, pE315-E322, 8p, 1 Color Photograph, 16 Graphs
- Publication Year :
- 2006
-
Abstract
- 1,25-Dihydroxyvitamin D [1,25(OH)<subscript>2</subscript>D<subscript>3</subscript>] 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<superscript>-/-</superscript> mice, the basal level of κB inhibitor (1κB) α protein was markedly decreased compared with VDR<superscript>+/-</superscript> MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR<superscript>-/-</superscript> 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<superscript>-/-</superscript> cells. In addition, the physical interaction between VDR and p65 was absent in VDR<superscript>-/-</superscript> 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<superscript>-/-</superscript> than in VDR<superscript>+/-</superscript> cells, indicating that VDR<superscript>-/-</superscript> 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<superscript>-/-</superscript> MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)<subscript>2</subscript>D<subscript>3</subscript>. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)<subscript>2</subscript>D<subscript>3</subscript> in VDR<superscript>+/-</superscript> cells, but not in VDR<superscript>-/-</superscript> cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation. [ABSTRACT FROM AUTHOR]
- Subjects :
- VITAMIN D
FIBROBLASTS
INFLAMMATION
MICE
Subjects
Details
- Language :
- English
- ISSN :
- 01931849
- Volume :
- 291
- Database :
- Complementary Index
- Journal :
- American Journal of Physiology: Endocrinology & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 21988226
- Full Text :
- https://doi.org/10.1152/ajpendo.00590.2005