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Vitamin D Up-Regulates the Vitamin D Receptor by Protecting It from Proteasomal Degradation

  • Martin Kongsbak-Wismann
  • Anna Kathrine Obelitz Rode
  • Marie Mathilde Hansen
  • Charlotte Menné Bonefeld
  • Carsten Geisler
Living reference work entry

Abstract

Vitamin D and the vitamin D receptor (VDR) play prominent roles in multiple aspects of human health and disease, and great interest is focused on the role that vitamin D might play in decreasing the risk of chronic illnesses such as autoimmune, infectious, and cardiovascular diseases. Humans normally get the majority of their vitamin D from exposure to sunlight. However, modern living and other cultural conditions limit our exposure to sunlight, and the frequency of people with vitamin D deficiency is generally high. Furthermore, the occurrence of vitamin D deficiency increases with age, i.e., due to a decreased capacity to produce vitamin D in old skin. The physiological actions of vitamin D are mediated by the VDR that functions as a ligand-induced transcription factor. The VDR is widely expressed by various cell types in the body, including many cells of the immune system, and vitamin D has strong immunomodulatory properties. The expression level of the VDR in cells is a key component for the cellular sensitivity to vitamin D, and vitamin D and VDR expression are consequently carefully regulated by a number of mechanisms. The VDR expression is modulated by the presence of its own ligand in most cell types. The typical response to vitamin D is up-regulation of VDR expression. This can in theory be caused by an increased rate of VDR synthesis and/or a decreased rate of receptor degradation. This chapter focus on how vitamin D up-regulates the VDR by protecting it from proteasomal degradation.

Keywords

Vitamin D Vitamin D receptor Proteasome Immune system T cell 

Introduction

During the early industrialization, an epidemic-like outburst of the bone-deforming disease rickets occurred in urban areas. Massive air pollution reduced the amount of sunlight reaching the ground, and it was later found that rickets could be cured by exposure of the patients to sunlight or treatment with special diets rich on vitamin D (Hess and Unger 1921; Hess et al. 1922; Holick 2004). Vitamin D was thus first recognized for its fundamental role in skeletal health and in maintaining calcium and phosphorous homeostasis (Holick 2007). The last decades have shown that vitamin D has diverse biologic actions and not only plays an important role in calcium and phosphorous homeostasis (Grober et al. 2013; Wacker and Holick 2013). The biologic actions of vitamin D are initiated through changes in gene expression that are mediated by the intracellular vitamin D receptor (VDR). It has become clear that most tissues and cells in the body express the VDR, and it is believed that vitamin D regulates up to 3–5% of our genes, including central genes of the immune system (Feldman et al. 2011).

Vitamin D Metabolism

Vitamin D is also known as “the sunshine vitamin” as humans normally acquire more than 90% of their vitamin D from the sun. During exposure to sunlight, ultraviolet B (UVB) radiation is absorbed by 7-dehydrocholesterol (7-DHC) present in the plasma membrane of the keratinocytes of the skin generating previtamin D3, which quickly is transformed into the stable vitamin D3 (cholecalciferol) (Grober et al. 2013) (Fig. 1). Vitamin D3 is ejected from the plasma membrane and subsequently bound by the serum carrier, vitamin D-binding protein (DBP). DBP is closely related to serum albumin and is found in the concentration of approximately 5 μM in serum (Feldman et al. 2011; Holick 2004, 2007). If vitamin D3 is not removed from the skin, further UVB absorption leads to formation of inactive photoisomers, a mechanism that prevents vitamin D3 intoxication following excessive sun exposure (Holick 2007). Very few foods such as fatty fish and some types of mushrooms contain relevant amounts of vitamin D naturally; however, some countries fortify foods such as milk, margarine, cereals, and juice with vitamin D (Feldman et al. 2011; Holick 2004). Two forms of vitamin D can be obtained by nutritional intake: vitamin D2 (ergocalciferol) and vitamin D3. Regardless of the form of vitamin D, it needs to be hydroxylated twice in order to become biologically active (Jones et al. 1998) (Fig. 1). Vitamin D can be taken up by cells of the liver, where the hepatic enzyme cytochrome P450 27A1 (CYP27A1) mediates the first hydroxylation of vitamin D, which results in formation of the inactive vitamin D, 25(OH)D3 (calcidiol) or 25(OH)D2 (25-hydroxyergocalciferol). DBP binds 25(OH)D and transports it to the kidneys, where the proximal tubular cells can endocytose the DBP-25(OH)D complex and perform a second hydroxylation resulting in the formation of 1,25(OH)2D3 (calcitriol) or 1,25(OH)2D2 (1,25-dihydroxyergocalciferol), the active forms of vitamin D (Fraser and Kodicek 1970). This hydroxylation step is mediated by the related enzyme cytochrome P450 27B1 (CYP27B1) (Takeyama et al. 1997). There is little evidence that the two active forms, 1,25(OH)2D3 and 1,25(OH)2D2, differ in their mode of action (Feldman et al. 2011). CYP27B1 was first found to be expressed in renal proximal tubular cells, and thus 1,25(OH)2D3 production has traditionally been ascribed to the kidneys (Takeyama et al. 1997). However, although the kidneys are the major source of circulating 1,25(OH)2D3, CYP27B1 is also expressed in many extrarenal cells, including cells of the immune system (Adams et al. 2009; Jeffery et al. 2012; Kongsbak et al. 2014a, b; Liu et al. 2006; Rowling et al. 2006; von Essen et al. 2010). As many cells also express the VDR, this means that 1,25(OH)2D3 can function both in an systemic endocrine and in an intracrine/paracrine manner. 1,25(OH)2D3 limits its own activity in the target cells by inducing a third cytochrome P450 enzyme called CYP24A1. CYP24A1 performs multiple steps of the C24-oxidation pathways that leads to the inactivation of 1,25(OH)2D3, thus preventing excessive vitamin D signaling (Beckman et al. 1996; Jones et al. 1998).
Fig. 1

Production and metabolism of vitamin D. Vitamin D3 is produced from conversion of 7-DHC in the skin through sunlight exposure. In the liver vitamin D3 is hydroxylated in position 25 generating 25(OH)D3. A second hydroxylation in position 1 produces the active form of vitamin D, 1,25(OH)2D3. This step mainly takes place in the kidneys; however, other tissues and cells expressing the enzyme CYP27B1 (1α-hydroxylase) also have the ability to produce 1,25(OH)2D3

Vitamin D Deficiency and Ageing

The parameter of choice for the assessment of the vitamin D status of an individual is the 25(OH)D (D2 plus D3) serum concentration. There still is no consensus on the optimal levels of serum 25(OH)D; however, vitamin D deficiency is by most experts defined as a 25(OH)D level below 50 nM (20 ng/ml) (Holick 2007; Lips 2010). According to this definition, it is estimated that between 30% and 50% of the general population have vitamin D deficiency (Holick 2007). The percentage of people with vitamin D deficiency increases with age (Chapuy et al. 1997; Glerup et al. 2000; Holick et al. 2005; Holick 2007; Lips 2001, 2010; McKenna 1992). One reason for the increase in the prevalence of vitamin D deficiency in the elderly might be the drop in 7-DHC in the skin and thereby the impaired capacity to produce vitamin D3 with age (MacLaughlin and Holick 1985). Vitamin D deficiency is likely to be an important factor in many chronic diseases (Grober et al. 2013; Holick 2007) and is associated with higher risk of infections such as tuberculosis (Nnoaham and Clarke 2008) and autoimmune diseases such as type 1 diabetes mellitus (Hypponen et al. 2001) and multiple sclerosis (Ascherio et al. 2010; Simpson et al. 2010). Recent studies have shown that vitamin D deficiency in women aged 75 years or older is associated with greater all-cause mortality (Buchebner et al. 2016) and that vitamin D and calcium reduce mortality in the elderly (Rejnmark et al. 2012).

Ageing is associated with impairment of lymphocyte telomerase, and a correlation between senescent T cells with shortened telomeres and age-associated pathologies and early death has been described (Calado and Young 2009; Cawthon et al. 2003; Macaulay et al. 2013; Najarro et al. 2015). Although senescent T cells lack CD28 and have alterations in their signaling pathways, they continue to function as a source of pro-inflammatory cytokines (Goronzy et al. 2012). Some evidence suggests that vitamin D might help reduce the rate of T-cell senescence as higher levels of vitamin D and vitamin D supplementation are associated with increased telomere length and CD28 expression (Liaskou et al. 2014; Richards et al. 2007; Zhu et al. 2012).

Vitamin D and the Immune System

Vitamin D is recognized as an important immunomodulatory agent that regulates the function of both the innate and the adaptive immune system (Baeke et al. 2010b; Bouillon et al. 2008; Hewison 2012; Peelen et al. 2011; Prietl et al. 2013; White 2012). Monocytes, macrophages, and dendritic cells (DC) express the VDR, and activation via toll-like receptor (TLR) signaling results in transcriptional induction of CYP27B1 in these cells (Adams et al. 2009; Jeffery et al. 2012; Liu et al. 2006). This enables the cells to convert 25(OH)D3 to the active 1,25(OH)2D3 and thereby to form 1,25(OH)2D3-VDR complexes (Chun et al. 2010). The 1,25(OH)2D3-VDR complexes subsequently act as transcriptional factors inducing expression of a range of genes including the genes for the antimicrobial peptides cathelicidin (hCAP18) and β-defensin 2 (DEFB4) (Gombart et al. 2005; Wang et al. 2004). In addition to their direct antimicrobial function, DC are central antigen-presenting cells (APC) and thereby play a key role in the activation of naïve T cells. Several studies indicate that vitamin D can induce the development of a tolerogenic type of DC characterized by decreased expression of MHC II and costimulatory molecules (Baeke et al. 2010b; Mora et al. 2008; Penna et al. 2007). Vitamin D also inhibits interleukin (IL)-12 and augments IL-10 secretion in activated DC (Penna and Adorini 2000; van Halteren et al. 2002).

The effects of vitamin D on DC indirectly affect activation and differentiation of T cells; however, T cells are also direct targets of 1,25(OH)2D3 as they express the VDR upon activation (Baeke et al. 2010a; Bhalla et al. 1983; Chen et al. 2005; Joseph et al. 2012; Kizaki et al. 1991; Kongsbak et al. 2014a; Provvedini et al. 1983; Provvedini and Manolagas 1989; von Essen et al. 2010; Yu et al. 1991a, b). Following activation, naïve CD4+ T cells differentiate into different types of effector cells that determine the nature of the immune response (Littman and Rudensky 2010; Murphy and Reiner 2002). In addition to cytokines, vitamin D is an important determinant in the differentiation of CD4+ effector T cells. Vitamin D inhibits interferon (IFN)-γ and augments IL-4 production, thereby restricting Th1 differentiation and promoting Th2 differentiation. Furthermore, vitamin D inhibits Th17 differentiation and promotes Treg induction (Correale et al. 2009; Jeffery et al. 2009; Joshi et al. 2011; Mora et al. 2008; Palmer et al. 2011; Peelen et al. 2011; Thien et al. 2005; Urry et al. 2012; van Etten and Mathieu 2005) (Fig. 2).
Fig. 2

Immunomodulatory effects of 1,25(OH)2D3 on T-cell differentiation. Following activation, T cells start to express both CYP27B1 and the VDR. The activated T cells can thus respond in both an autocrine and a paracrine manner to vitamin D. Vitamin D inhibits Th1 and Th17 differentiation and promotes Th2 and Treg differentiation

The Vitamin D Receptor

The cellular actions of 1,25(OH)2D3 are mediated through its binding to the VDR (Haussler and Norman 1969). The VDR is a member of the nuclear receptor family of transcription factors (Baker et al. 1988), and it is characterized as being a ligand-dependent transcription factor for various target genes. 1,25(OH)2D3 binds the VDR with high affinity with Kds reported to be 30 × 10−10 M (Kream et al. 1977), 6–8 × 10−10 M (Pike and Haussler 1983), and 22 × 10−10 M (Li et al. 1999), respectively. 1,25(OH)2D3 induces conformational changes in the VDR (Rochel et al. 2000) and translocation of the 1,25(OH)2D3-VDR complex to the nucleus (Gocek et al. 2007; Hsieh et al. 1991; Klopot et al. 2007; Pike and Haussler 1983). Within the nucleus 1,25(OH)2D3-VDR, complexes bind to various interaction partners with the retinoid X receptor (RXR) being the most well-described. Interaction with RXR increases the affinity of the complex for DNA binding (Kliewer et al. 1992; Long et al. 2015). The DNA sequences bound by 1,25(OH)2D3-VDR-RXR complexes are called vitamin D response elements (VDRE). VDRE comprise two hexameric nucleotide repeats separated by a spacer of three or six nucleotides referred to as a DR3- or DR6-type element, respectively (Haussler et al. 2013; Li et al. 1997). Binding of 1,25(OH)2D3-VDR-RXR complexes to VDRE results in gene regulation through several mechanisms. The complex can recruit various cofactors with chromatin structure modulating properties. Depending on the target gene, either coactivators or corepressors are attracted to the complex to induce or repress gene transcription (Jones et al. 1998) (Fig. 3). In addition to regulation through the VDRE of target genes, the VDR can inhibit the expression of some genes by antagonizing the action of other transcription factors such as NFAT (Nagpal et al. 2005). An example is inhibition of the cytokine IL-2. Here, 1,25(OH)2D3-VDR-RXR complexes compete with NFAT for binding to the distal NFAT-binding site in the human IL-2 promoter resulting in transcriptional repression of the IL-2 gene (Alroy et al. 1995; Nagpal et al. 2005; Takeuchi et al. 1998) (Fig. 3).
Fig. 3

Gene regulation by 1,25(OH)2D3-VDR-RXR complexes. Binding of the VDR to its ligand 1,25(OH)2D3 enables dimerization of the VDR and RXR, allowing binding of the 1,25(OH)2D3-VDR-RXR complex to VDRE in 1,25(OH)2D3-responsive genes. Binding of 1,25(OH)2D3-VDR-RXR complexes to VDRE is accompanied by formation of a large complex including either coactivators or corepressors leading to induction or inhibition of target genes, respectively. Alternatively, the 1,25(OH)2D3-VDR-RXR complex can compete with other transcription factors for binding to specific DNA-binding sites

VDR Gene and Protein Regulation

The response to 1,25(OH)2D3 correlates with the expression level of the VDR protein in a given cell (Chen et al. 1986; Li et al. 1999; Walters et al. 1982). VDR expression differs with the type and differentiation of the cell and is modulated by many stimuli including signals from hormones, retinoids, and growth factors (Bouillon et al. 2008; Kongsbak et al. 2013). VDR expression is furthermore modulated by the presence of its own ligand 1,25(OH)2D3 in some cell types. Regulation of a receptor by its own ligand is often called homologous regulation or autoregulation. Up-regulation of VDR expression is the typical response to 1,25(OH)2D3. This can in theory be caused by an increased rate of VDR synthesis as suggested in some studies and supported by the presence of VDRE in the VDR gene (Costa et al. 1985; Healy et al. 2005; Mangelsdorf et al. 1987; Pan and Price 1987; Tiosano et al. 2013; Zella et al. 2010) and/or a decreased rate of receptor degradation, e.g., by stabilization of the VDR as suggested by others (Davoodi et al. 1995; Healy et al. 2005; Jaaskelainen et al. 2000; Kaiser et al. 2013; Kongsbak et al. 2014a; Li et al. 1999; Peleg and Nguyen 2010; Santiso-Mere et al. 1993; Wiese et al. 1992) (Table 1).
Table 1

The effect of vitamin D and proteasome inhibitors on VDR expression

Cell

VDR mRNA

mRNA detection

VDR protein

Protein detection

Reference

LLC-PK (pig kidney cell line) and human fibroblasts

Not tested

↑ 1,25(OH)2D3 increased VDR expression two- to fourfold

Ligand-binding assay

(Costa et al. 1985)

ROS 17/2 (rat osteosarcoma cell line)

Not tested

↑ 1,25(OH)2D3 increased VDR expression tenfold

Ligand-binding assay

(Pan and Price 1987)

3 T6 (mouse fibroblast cell line)

↑ 1,25(OH)2D3 increased VDR mRNA levels

Northern blot

↑ 1,25(OH)2D3 increased VDR expression five- to tenfold

Ligand-binding assay

(McDonnell et al. 1987)

LLC-PK (pig kidney cell line)

Not tested

↑ 1,25(OH)2D3 increased VDR expression threefold

Density shift

(Costa and Feldman 1987)

Human monocytes in vivo

Not tested

↑ 1,25(OH)2D3 increased VDR expression three- to tenfold

Ligand-binding assay

(Merke et al. 1989)

NIH 3 T6 (mouse embryonic fibroblast cell line) and

IEC-6 (rat intestinal epithelial cell line)

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

RNase protection assay

↑ 1,25(OH)2D3 increased VDR expression two- to threefold

Immunoradiometric assay

(Wiese et al. 1992)

Human monocytes

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

Northern blot

↑ 1,25(OH)2D3 increased VDR expression two- to threefold

Ligand-binding assay

(Kreutz et al. 1993)

COS-1 (African green monkey fibroblast cell line) and yeast

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

Northern blot

↑ 1,25(OH)2D3 increased VDR expression 5–14-fold

WB

(Santiso-Mere et al. 1993)

ROS 17/2.8 (rat osteosarcoma cell line)

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

RNase protection assay

↑ 1,25(OH)2D3 increased VDR expression fivefold

Immunoradiometric assay and WB

(Arbour et al. 1993)

MG-63 (human osteosarcoma cell line)

↑ 1,25(OH)2D3 increased VDR mRNA levels

Northern blot

↑ 1,25(OH)2D3 increased VDR expression

Immunoprecipitation

(Mahonen and Maenpaa 1994)

T-47D (human breast cancer cell line)

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

RNase protection assay

↑ 1,25(OH)2D3 increased VDR expression three- to sevenfold

Ligand-binding assay

(Davoodi et al. 1995)

ROS 17/2.8 (rat osteosarcoma cell line)

Not tested

1,25(OH)2D3 inhibits VDR degradation

Immunoradiometric assay

(van den Bemd et al. 1996)

Human skin and keratinocytes

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

QPCR

↑ 1,25(OH)2D3 increased VDR expression twofold in both intact skin and keratinocytes. Proteasome inhibitors increased VDR expression

 

(Li et al. 1999)

MG-63 (human osteoblastic sarcoma cell line)

Not tested

↑ 1,25(OH)2D3 increased VDR expression. MG132 increased VDR expression

WB

(Jaaskelainen et al. 2000)

TCMK-1 (mouse kidney cell line)

↑ 1,25(OH)2D3 increased VDR mRNA levels four- to fivefold

QPCR

↑ 1,25(OH)2D3 increased VDR expression four- to fivefold

ELISA

(Healy et al. 2005)

MC3T3-E3 (mouse osteoblastic cell line)

↑ 1,25(OH)2D3 increased VDR mRNA levels

QPCR

Not tested

 

(Zella et al. 2006)

Human mesenchymal stem cells

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

QPCR

↑ 1,25(OH)2D3 increased VDR expression. Bortezomib increased VDR expression

WB

(Kaiser et al. 2013)

Primary naïve human CD4+ T cells

− 1,25(OH)2D3 did not significantly affect VDR mRNA levels

QPCR

↑ 1,25(OH)2D3 increased VDR expression twofold

Lactacystin inhibited VDR degradation

WB

(Kongsbak et al. 2014a)

H1299 (human lung adenocarcinoma cell line)

Not tested

↑ MG132 inhibited VDR degradation

WB

(Heyne et al. 2015)

In 1985 Costa et al. set out to examine whether vitamin D metabolites autoregulated the VDR. They examined pig kidney cells and human fibroblast and determined the amount of VDR by ligand binding assays. They observed that various vitamin D metabolites increased the VDR number according to their affinity for the VDR (Costa et al. 1985). The increase in VDR expression could be divided in a rapid phase that was independent on the presence of the transcriptional inhibitor actinomycin D and a slower phase that was sensitive to actinomycin D. They suggested that up-regulation of the VDR in the rapid phase was caused by stabilization of the VDR by its ligand and that the additional VDR up-regulation in the slower phase was dependent on RNA synthesis. In a later study also on pig kidney cells, they could conclude that up-regulation of the VDR by 1,25(OH)2D3 predominantly resulted from stabilization of the VDR in addition to a relatively smaller increase in the rate of VDR synthesis. They found that the half-life (t½) of the VDR in the absence of 1,25(OH)2D3 was approximately 4.3 hours (h), whereas it was prolonged to approximately 8.9 h in the presence of 1,25(OH)2D3 (Costa and Feldman 1987). In contrast, Pan and Price found that 1,25(OH)2D3-induced VDR up-regulation in the rat osteosarcoma cell line ROS 17/2.8 was not caused by stabilization of the VDR but by induction of VDR gene expression. They found the t½ of the VDR was unaffected by 1,25(OH)2D3 with t½ of approximately 2.7 and 2.5 h in the absence and presence of 1,25(OH)2D3, respectively, but that the RNA polymerase II inhibitor α-amanitin significantly inhibited VDR up-regulation (Pan and Price 1987). However, later studies performed in the same cell line contradicted the results by Pan and Price. Thus, Arbour et al. found that the t½ of the VDR in ROS 17/2.8 cells was 2 h in the absence of 1,25(OH)2D3 and that 1,25(OH)2D3 increased the t½ to more than 6 h, and furthermore they found that 1,25(OH)2D3 did not affect the level of VDR mRNA (Arbour et al. 1993). That 1,25(OH)2D3 stabilizes the VDR in ROS 17/2.8 cells was further confirmed by van den Bemd et al., who found that the t½ of the VDR in ROS 17/2.8 cells increased from 1.5 h in the absence of 1,25(OH)2D3 to 13.5 h in the presence of 1,25(OH)2D3 (van den Bemd et al. 1996).

Studies in the mouse 3 T6 fibroblast cell line confirmed that 1,25(OH)2D3 significantly up-regulates the VDR. One study found a parallel up-regulation in VDR protein and VDR mRNA and, without investigating whether 1,25(OH)2D3 stabilized the VDR, concluded that 1,25(OH)2D3 up-regulates the VDR via a direct increase in VDR mRNA (McDonnell et al. 1987). In contrast, Wiese et al. found that 1,25(OH)2D3-induced VDR up-regulation predominantly was caused by stabilization of the VDR in addition to a small increase in the VDR mRNA levels. The t½ of the VDR in 3 T6 cells was thus found to increase from 4 h in the absence to 8 h in the presence of 1,25(OH)2D3 (Wiese et al. 1992). Studies on the effect of 1,25(OH)2D3 on VDR expression in vivo showed that VDR expression increased approximately threefold in human monocytes 24 h after oral administration of 1.5 μg 1,25(OH)2D3 (Merke et al. 1989). The same group later demonstrated that 1,25(OH)2D3 up-regulated the VDR in monocytes by stabilizing the receptor and not by affecting the level of VDR mRNA (Kreutz et al. 1993)

Thus, a general consensus has been reached that 1,25(OH)2D3 up-regulates VDR protein expression (Table 1). The majority of studies found that VDR protein up-regulation was not paralleled by up-regulation of VDR mRNA (Arbour et al. 1993; Davoodi et al. 1995; Kaiser et al. 2013; Kongsbak et al. 2014a; Kreutz et al. 1993; Li et al. 1999; Santiso-Mere et al. 1993; Wiese et al. 1992), whereas some studies found that VDR protein up-regulation was paralleled by VDR mRNA up-regulation (Healy et al. 2005; Mahonen and Maenpaa 1994; McDonnell et al. 1987; Zella et al. 2006).

The underlying mechanism behind 1,25(OH)2D3-induced up-regulation of VDR protein expression is most likely that binding of 1,25(OH)2D3 to the VDR protects the VDR against proteasomal degradation. Li et al. found that the VDR in human keratinocytes was ubiquitinated and that this ubiquitination was inhibited by 1,25(OH)2D3 and furthermore that 1,25(OH)2D3 and proteasome inhibitors increased VDR expression without affecting VDR mRNA levels (Li et al. 1999). Co-treatment with 1,25(OH)2D3 and the proteasome inhibitor MG132 inhibited VDR degradation slightly more than treatment with each of the substances alone. This could suggest that 1,25(OH)2D3 not fully protected the VDR against proteasomal degradation, that 1,25(OH)2D3 in addition to the degradation in the proteasome also protected the VDR against degradation by other pathways or maybe more likely, that the concentration of proteasome inhibitor used not completely inhibited proteasome-mediated VDR degradation. Another study found that MG132 increased the VDR levels 2.5-fold in the human osteoblastic sarcoma cell line MG-63, when they were not treated with 1,25(OH)2D3 (Jaaskelainen et al. 2000). Treatment of MG-63 cells with 1,25(OH)2D3 increased the VDR levels to a similar extent as treatment with MG132; however, the 1,25(OH)2D3-induced increase in VDR expression was not further increased by simultaneous treatment with MG132. This indicated that 1,25(OH)2D3 fully protected the VDR against proteasomal degradation in MG-63 cells. In accordance, treatment with MG132 inhibited VDR degradation in ROS 17/2.8 cells and the 1,25(OH)2D3-induced increase in VDR expression was not further augmented by simultaneous treatment with MG132 (Masuyama and MacDonald 1998). In contrast to these studies, Kaiser et al. found that partial inhibition of the proteasome activity with bortezomib strongly increased 1,25(OH)2D3-induced VDR up-regulation in human mesenchymal stem cells (Kaiser et al. 2013). Whether special conditions in mesenchymal stem cells could explain this controversial finding needs further investigations. Studies of the VDR in human primary T cells demonstrated that the VDR is spontaneously degraded with a t½ of 1.7 h in untreated cells and that 1,25(OH)2D3 stabilized the VDR and increased its t½ to 2.9 h (Kongsbak et al. 2014a). The spontaneous degradation of the VDR could be completely blocked by treating the cells with 10 μM of the proteasome inhibitor lactacystin, and it was conclusively demonstrated that 1,25(OH)2D3 protects the VDR against proteasomal degradation in T cells (Kongsbak et al. 2014a).

Studies in other cells than T cells have shown that the VDR shuttles between the cytosol and the nucleus. In general, the VDR is distributed to both the cytosol and the nucleus in the absence of 1,25(OH)2D3, and 1,25(OH)2D3 increases the localization of the VDR to the nucleus in most cell types studied (Haussler et al. 2013; Klopot et al. 2007; Nagpal et al. 2005; Prufer et al. 2000). Kongsbak et al. found that the VDR distributes with approximately 35% in the cytosol and 65% in the nucleus in activated T cells in the absence of 1,25(OH)2D3 (Fig. 4). A significant redistribution of the VDR resulting in localization of more than 90% of the VDR in the nucleus was seen after addition of 1,25(OH)2D3 (Kongsbak et al. 2014a). Nuclear import of the VDR seems to be important for stabilization of the VDR in osteoblasts (Peleg and Nguyen 2010). The major route of disposal for most cytosolic and nuclear proteins is the ubiquitin-proteasome pathway (Schwartz and Ciechanover 2009; von Mikecz 2006), and interestingly Kongsbak et al. found that blocking the proteasome activity augmented the VDR t½ and expression equally in the cytosol and nucleus of T cells (Fig. 4). To determine where the VDR was degraded, they studied the effect of leptomycin B (LMB) known to inhibit the nuclear export of many molecules including p53 (Freedman and Levine 1998; Hutten and Kehlenbach 2007). It has been reported that LMB blocks the nuclear export of unliganded VDR-GFP chimeras in transfected cell lines (Prufer and Barsony 2002); however, Kongsbak et al. demonstrated that LMB does not inhibit nuclear export nor affects degradation of the VDR in T cells. Consequently, they could not determine the primary site for VDR degradation. However, they could conclude that the spontaneous proteasomal degradation of the VDR was inhibited by 1,25(OH)2D3 that thereby increases the half-life of the VDR in T cells. These results were in good agreement with the observation that 1,25(OH)2D3 inhibits ubiquitination and thereby proteasomal degradation of the VDR in keratinocytes (Li et al. 1999) and in Cos-1 cells (Peleg and Nguyen 2010). The proteasomal degradation of the VDR might be inhibited by 1,25(OH)2D3 by its induction of conformational changes of the VDR either directly or by the association of VDR and RXR. Alternatively, 1,25(OH)2D3 might influence VDR degradation by regulating the expression of molecules involved in VDR degradation such as SUG1 (Masuyama and MacDonald 1998), CDK11B (Chi et al. 2009) and MDM2 (Heyne et al. 2015).
Fig. 4

VDR localization, half-life, and degradation in T cells. In the absence (A) of 1,25(OH)2D3, the VDR are distributed with approximately 35% in the cytoplasm and 65% in the nucleus. 1,25(OH)2D3 induces a substantial redistribution with approximately 5% of the VDR in the cytoplasm and 95% in the nucleus (B). 1,25(OH)2D3 increases the t½ approximately twofold of both the cytoplasmic and nuclear fraction of VDR. Leptomycin B that inhibits nuclear export of several nuclear proteins including p53 does not affect VDR distribution or degradation in T cells

The underlying mechanism behind the 1,25(OH)2D3-induced up-regulation of VDR mRNA expression observed in some studies is supported by the existence of VDRE in the VDR gene (Zella et al. 2006, 2010). However, transcriptomic studies focusing on the protein coding mRNA that is regulated by 1,25(OH)2D3-VDR have established the surprising diversity of the VDR transcriptome, revealing it to be highly heterogeneous and cell type- and time-dependent. It is therefore likely that the divergent observations concerning 1,25(OH)2D3-induced up-regulation of VDR mRNA is caused by studies of the phenomenon in different types of cells, where some types of cells have and others have not the machinery available to allow 1,25(OH)2D3-induced VDR mRNA up-regulation.

Conclusions and Future Directions

Vitamin D has strong immunomodulatory properties and affects T-cell differentiation and function. The expression level of the VDR in cells is a key component for the cellular sensitivity to vitamin D, and vitamin D and VDR expression are carefully regulated by a number of mechanisms. In most cell types, the typical response to vitamin D is up-regulation of VDR expression. General consensus has been reached that the underlying mechanism behind 1,25(OH)2D3-induced up-regulation of VDR protein expression is that binding of 1,25(OH)2D3 to the VDR protects the VDR against proteasomal degradation. In some types of cells, the 1,25(OH)2D3-induced up-regulation of VDR protein expression is paralleled by an up-regulation of VDR mRNA in concordance with the existence of VDRE in the VDR gene. To precisely determine the mechanisms by which 1,25(OH)2D3 inhibits the proteasomal degradation of the VDR and to determine whether manipulation of the VDR expression level in a given cell is possible and whether this could have therapeutic consequences require future studies.

Cross-References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Martin Kongsbak-Wismann
    • 1
  • Anna Kathrine Obelitz Rode
    • 1
  • Marie Mathilde Hansen
    • 1
  • Charlotte Menné Bonefeld
    • 1
  • Carsten Geisler
    • 1
  1. 1.Department of Immunology and Microbiology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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