1,25-Dihydroxyvitamin D3 Is an Autonomous Regulator of the Transcriptional Changes Leading to a Tolerogenic Dendritic Cell Phenotype

Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
The Journal of Immunology (Impact Factor: 4.92). 03/2009; 182(4):2074-83. DOI: 10.4049/jimmunol.0803345
Source: PubMed


Activation of vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D(3) (1,25-vitD) reprograms dendritic cells (DC) to become tolerogenic. Previous studies suggested that 1,25-vitD could inhibit the changes brought about by differentiation and maturation of DCs. Underpinning the described phenotypic and functional alterations, there must be 1,25-vitD-coordinated transcriptional events. However, this transcriptional program has not been systematically investigated, particularly not in a developmental context. Hence, it has not been explored how 1,25-vitD-regulated genes, particularly the ones bringing about the tolerogenic phenotype, are connected to differentiation. We conducted global gene expression analysis followed by comprehensive quantitative PCR validation to clarify the interrelationship between 1,25-vitD and differentiation-driven gene expression patterns in developing human monocyte-derived and blood myeloid DCs. In this study we show that 1,25-vitD regulates a large set of genes that are not affected by differentiation. Interestingly, several genes, impacted both by the ligand and by differentiation, appear to be regulated by 1,25-vitD independently of the developmental context. We have also characterized the kinetics of generation of 1,25-vitD by using three early and robustly regulated genes, the chemokine CCL22, the inhibitory receptors CD300LF and CYP24A1. We found that monocyte-derived DCs are able to turn on 1,25-vitD sensitive genes in early phases of differentiation if the precursor is present. Our data collectively suggest that exogenous or endogenously generated 1,25-vitD regulates a large set of its targets autonomously and not via inhibition of differentiation and maturation, leading to the previously characterized tolerogenic state.

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    • "In order to elucidate the molecular mechanisms underlying the tolerogenic properties of 1,25D 3 -DCs, we performed microarray analysis of human dMo at 4 and 24 hr after addition of differentiation media (e.g., IL-4 and granulocyte macrophage colonystimulating factor [GM-CSF]) and 1,25(OH) 2 D 3 (10 À8 M) (Figure S1). These early time points were chosen based on the observation that a single dose of 1,25(OH) 2 D 3 to dMo at the start of the in vitro DC culture was sufficient to generate the tolerogenic profile, because we observed a similar decrease in CD80/HLA-DR and an increase in CD14 surface expression, when compared to DCs exposed to two administrations of 1,25(OH) 2 D 3 (Szé les et al., 2009; Figure S2). Four hours of treatment with 1,25(OH) 2 D 3 induced the differential expression of 100 genes, compared to controls (1.3-fold change; adjusted p < 0.01) (Figure S3A, left panel). "
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    ABSTRACT: Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3 upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)2D3-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)2D3, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 02/2015; 10(5). DOI:10.1016/j.celrep.2015.01.013 · 8.36 Impact Factor
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    • "These studies have focused primarily on the effects of 1,25D and its synthetic analogs on DCs, with results underlining the ability of 1,25D to promote decreased antigen presentation and a tolerogenic phenotype in these cells (Griffin et al., 2004; Shen and Zheng, 2004; Pedersen et al., 2009; Szeles et al., 2009). Notably, one of these array studies showed that the effects of 1,25D on DC gene expression were independent of DC differentiation status, suggesting a specific role for 1,25D as a regulator of DC function (Szeles et al., 2009). This particular study also reported that key changes in DC gene expression could be achieved using either 1,25D or 25D, further emphasizing the functional importance of the intracrine vitamin D system in these cells. "
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    ABSTRACT: Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.
    Frontiers in Physiology 04/2014; 5:151. DOI:10.3389/fphys.2014.00151 · 3.53 Impact Factor
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    • "Phylogenetic analysis of the HERC family revealed that the HERC4 ancestor emerged in nematodes and that the HERC family expanded to six members during animal evolution, with HERC5 being the most recently emerged family member [4]. HERC5 is ubiquitously expressed in many cell types and tissues including, but not limited to, effector and central memory T cells, dendritic cells, CD14+ monocytes, monocyte-derived macrophages, embryonic and induced pluripotent stem cells, hematopoietic and granulopoietic stem cells, testis (germ and leydig cells), ovary, liver and lung [5-17]. HERC5 expression is up-regulated in response to IFN [18,19], in vitro and in vivo virus infection [1,20-25], lipopolysaccharide, tumor necrosis factor α, and interleukin-1β [26]. "
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