title: Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells.
abstract: 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.
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Kongsbak
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marina R
authors.initials: MR
authors.lastname: von Essen
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Boding
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Trine B
authors.initials: TB
authors.lastname: Levring
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens P H
authors.initials: JP
authors.lastname: Lauritsen
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.affiliation: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002117:Calcitriol / Q000276:immunology*; D002478:Cells, Cultured; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008213:Lymphocyte Activation; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D015704:CD4 Antigens; D065692:Cytochrome P-450 CYP3A Inhibitors; D005231:Fatty Acids, Unsaturated; D061988:Proteasome Inhibitors; D018167:Receptors, Calcitriol; D046988:Proteasome Endopeptidase Complex; D002117:Calcitriol; D007654:Ketoconazole; C038753:leptomycin B