Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 42, Issue 2, Pages 329-336Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2009.11.012
Keywords
Vitamin D; Vitamin D receptor; I kappa B alpha; Inflammation; NF-kappa B
Categories
Funding
- NIDDK [KO1 DK075386]
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Vitamin D receptor plays an essential role in the regulation of inflammation. Previous studies demonstrate that vitamin D receptor negatively modulates the proinflammatory NF-kappa B pathway. However, it is unknown how vitamin D receptor regulates I kappa B alpha, the endogenous inhibitor of NF-kappa B Here we investigated the molecular mechanism of vitamin D receptor deletion and I kappa B alpha expression. We found that cells lacking vitamin D receptor had significantly increased levels of I kappa B alpha mRNA and simultaneously decreased levels Of I kappa B alpha protein. Lacking vitamin D receptor abolished its binding to the I kappa B alpha promoter. Moreover, the levels of protein translation regulators and the rate of protein synthesis were both decreased in cells lacking vitamin D receptor. At the post-translational level, I kappa B alpha ubiquitination was enhanced, indicating increased degradation of I kappa B alpha in the absence of vitamin D receptor. We further transfected cells with a plasmid carrying either wild-type or mutant I kappa B alpha. The expression of wild-type I kappa B alpha was much higher in the cells with vitamin D receptor than in the cells without vitamin D receptor, whereas the expression of exogenous I kappa B alpha was equally high in both cell lines. In summary, vitamin D receptor deletion affects I kappa B alpha through mRNA transcription, protein translation, protein-protein interaction, post-translational modification, and protein degradation, thus reducing the level Of I kappa B alpha protein. Cells lacking vitamin D receptor are known in a proinflammatory state with activation of NF-kappa B. Our study provides new insight into vitamin D receptor regulation of an inhibitor of NF-kappa B in inflammation. Deletion of vitamin D receptor contributes to the activation of NF-kappa B on multiple levels. (C) 2009 Elsevier Ltd. All rights reserved.
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