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

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

doi:10.1371/journal.pone.0096695

Cited by 69 publications

(77 citation statements)

References 72 publications

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“…We found that 1,25(OH) 2 D 3 strongly inhibited IFNγ production (~15-fold) at physiological concentrations (60–110 pM) (Figure 1A). Furthermore, we found that 25(OH)D 3 at physiological concentrations (50–125 nM) inhibited IFNγ production to the same degree as 1,25(OH) 2 D 3 (Figure 1A), which confirms that T cells have the ability to convert the inactive 25(OH)D 3 to the active 1,25(OH) 2 D 3 (46, 47). It is well known that anti-CD3/CD28 bead stimulation promotes expansion of CD4 + T cells (48).…”

Section: Resultssupporting

confidence: 62%

Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion

et al. 2017

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Tuberculosis (TB) presents a serious health problem with approximately one-third of the world’s population infected with Mycobacterium tuberculosis in a latent state. Experience from the pre-antibiotic era and more recent clinical studies have established a beneficial role of sunlight and vitamin D in patients with TB. At the same time, experimental data have shown that Th1 cells through production of IFNγ are crucial for cathelicidin release by macrophages, bacterial killing, and containment of M. tuberculosis in granulomas. Paradoxically, vitamin D has repeatedly been ascribed an immune-suppressive function inhibiting Th1 differentiation and production of IFNγ in T cells. The aim of this study was to investigate this apparent paradox. We studied naïve human CD4+ T cells activated either with CD3 and CD28 antibodies or with allogeneic dendritic cells (DC) stimulated with heat-killed M. tuberculosis (HKMT) or purified toll-like receptor (TLR) ligands. We show that vitamin D does not block differentiation of human CD4+ T cells to Th1 cells and that interleukin (IL)-12 partially counteracts vitamin D-mediated inhibition of IFNγ production promoting production of equal amounts of IFNγ in Th1 cells in the presence of vitamin D as in T cells activated in the absence of vitamin D and IL-12. Furthermore, we show that HKMT and TLR2 ligands strongly downregulate cathelicidin expression in DC and that vitamin D counteracts this by upregulating cathelicidin expression. In conclusion, we demonstrate that vitamin D counteracts M. tuberculosis-induced cathelicidin downregulation and allows Th1 differentiation and IFNγ secretion.

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Section: Resultssupporting

confidence: 62%

Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion

et al. 2017

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“…There have been conflicting results regarding the expression of VDR in non‐stimulated CD4 + T cells. Some studies have reported VDR expression in non‐stimulated T cells , whereas other studies have reported no VDR expression . Our results support the low expression of VDR in unstimulated CD4 + T cells.…”

Section: Discussionsupporting

confidence: 88%

Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn's disease

Bendix

Dige

Dahlerup

et al. 2015

Clinical and Experimental Immunology

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SummaryCrohn's disease (CD) is a chronic inflammatory disease associated with a dysregulated T cell response towards intestinal microflora. Vitamin D has immune modulatory effects on T cells through the nuclear vitamin D receptor (VDR) in vitro. It is unclear how oral vitamin D treatment affects VDR expression. The aim of this study was to establish a flow cytometry protocol, including nuclear and cytoplasmic VDR expression, and to investigate the effects of vitamin D treatment on T cell VDR expression in CD patients. The flow cytometry protocol for VDR staining was developed using the human acute monocytic leukaemia cell line (THP-1). The protocol was evaluated in anti-CD3/CD28-stimulated peripheral blood mononuclear cells (PBMCs) from vitamin D3-(n = 9) and placebo-treated (n = 9) CD patients. Anti-VDR-stained PBMCs were examined by flow cytometry, and their cytokine production was determined by cytokine bead array. VDR, CYP27B1 and RXRa mRNA expression levels in CD4 1 T cells were measured by quantitative reverse transcriptase polymerase chain reaction. The flow cytometry protocol enabled detection of cytoplasmic and nuclear VDR expression. The results were confirmed by confocal microscopy and supported by correlation with VDR mRNA expression. VDR expression in CD4 1 T cells increased following stimulation. This VDR up-regulation was inhibited with 30% by vitamin D treatment compared to placebo in CD patients (P = 0Á027). VDR expression was correlated with in-vitro interferon-g production in stimulated PBMCs (P = 0Á01). Flow cytometry is a useful method with which to measure intracellular VDR expression. Vitamin D treatment in CD patients reduces T cell receptor-mediated VDR up-regulation.

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“…Calcitriol targets also included genes involved in a variety of metabolic, detoxification, nuclear receptor‐related, and other pathways (Table S3). Supporting post‐translational regulation by vitamin D, as described in several systems , VDR was not identified as a significant regulated gene in the RNA‐seq analysis.…”

Section: Resultsmentioning

confidence: 78%

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

et al. 2019

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Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25‐dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness‐related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness‐related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

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

Cited by 69 publications

References 72 publications

Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion

Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion

Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn's disease

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

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