Vitamin D Up-Regulates the Vitamin D Receptor by Protecting It from Proteasomal Degradation in Human CD4.sup.+ T Cells

• Published in: PloS one 2014-05, Vol.9 (5)
• Main Authors: Kongsbak, Martin, von Essen, Marina R, Boding, Lasse, Levring, Trine B, Schjerling, Peter, Lauritsen, Jens P. H, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M, Geisler, Carsten
• Format: Article
• Language: English
• Subjects: RNA; T cells; Vitamin D
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096695

The active form of vitamin D.sub.3, 1,25(OH).sub.2 D.sub.3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4.sup.+ effector T cells. The biological actions of 1,25(OH).sub.2 D.sub.3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH).sub.2 D.sub.3 by itself regulates VDR expression in human CD4.sup.+ T cells. We found that activated CD4.sup.+ T cells have the capacity to convert the inactive 25(OH)D.sub.3 to the active 1,25(OH).sub.2 D.sub.3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH).sub.2 D.sub.3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4.sup.+ T cells. Furthermore, 1,25(OH).sub.2 D.sub.3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH).sub.2 D.sub.3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH).sub.2 D.sub.3 -induced gene activation. In conclusion, our study shows that activated CD4.sup.+ T cells can produce 1,25(OH).sub.2 D.sub.3, and that 1,25(OH).sub.2 D.sub.3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4.sup.+ T cells by protecting the VDR against proteasomal degradation.