Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells

• Published in: PloS one 2014-05, Vol.9 (5), p.e96695
• 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: Antifungal Agents - pharmacology; Autoimmune diseases; Biological effects; Biology and Life Sciences; Bone surgery; Calcitriol; Calcitriol - immunology; CD4 antigen; CD4 Antigens - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cells, Cultured; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Degradation; Effector cells; Fatty Acids, Unsaturated - pharmacology; Gene expression; Growth factors; Humans; Immune system; Immunoglobulins; Immunology; Immunomodulation; Ketoconazole - pharmacology; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Proteasome Endopeptidase Complex - immunology; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteasomes; Protein expression; Protein folding; Protein Transport - drug effects; Proteins; Proteolysis - drug effects; Receptors, Calcitriol - genetics; Receptors, Calcitriol - immunology; Receptors, Calcitriol - metabolism; Rodents; Studies; T cell receptors; Up-Regulation - drug effects; Vitamin D; Vitamin D receptors; Vitamin D3; Vitamin deficiency
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096695

The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 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)2D3 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)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 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)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation.