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

Martin Kongsbak; Marina R von Essen; Lasse Boding; Trine B Levring; Peter Schjerling; Jens P H Lauritsen; Anders Woetmann; Niels Ødum; Charlotte M Bonefeld; Carsten Geisler

doi:10.1371/journal.pone.0096695

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

Martin Kongsbak, Marina R von Essen, Lasse Boding, Trine B Levring, Peter Schjerling, Jens P H Lauritsen, Anders Woetmann, Niels Ødum, Charlotte M Bonefeld, Carsten Geisler

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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.

Originalsprog	Engelsk
Artikelnummer	e96695
Tidsskrift	PLOS ONE
Vol/bind	9
Udgave nummer	5
Sider (fra-til)	1-12
Antal sider	13
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0096695
Status	Udgivet - 2 maj 2014

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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.",

author = "Martin Kongsbak and {von Essen}, {Marina R} and Lasse Boding and Levring, {Trine B} and Peter Schjerling and Lauritsen, {Jens P H} and Anders Woetmann and Niels {\O}dum and Bonefeld, {Charlotte M} and Carsten Geisler",

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AU - Kongsbak, Martin

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AU - Boding, Lasse

AU - Levring, Trine B

AU - Schjerling, Peter

AU - Lauritsen, Jens P H

AU - Woetmann, Anders

AU - Ødum, Niels

AU - Bonefeld, Charlotte M

AU - Geisler, Carsten

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AB - 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.

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

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