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

The active form of vitamin D-3, 1,25(OH)(2)D-3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4(+) effector T cells. The biological actions of 1,25(OH)(2)D-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)(2)D-3 by itself regulates VDR expression in human CD4(+) T cells. We found that activated CD4(+) T cells have the capacity to convert the inactive 25(OH)D-3 to the active 1,25(OH)(2)D-3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)(2)D-3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4(+) T cells. Furthermore, 1,25(OH)(2)D-3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)(2)D-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)(2)D-3-induced gene activation. In conclusion, our study shows that activated CD4(+) T cells can produce 1,25(OH)(2)D-3, and that 1,25(OH)(2)D-3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4(+) T cells by protecting the VDR against proteasomal degradation.