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1,25-Dihydroxyvitamin D₃ Is an Autonomous Regulator of the Transcriptional Changes Leading to a Tolerogenic Dendritic Cell Phenotype^1,2

Lajos Széles^*,, Gábor Keresztes^*, Dániel Töröcsik^*, Zoltán Balajthy^*, László Krenács, Szilárd Póliska^*, Andreas Steinmeyer, Ulrich Zuegel^¶, Monika Pruenster^||, Antal Rot^|| and László Nagy^3,*,

^* Department of Biochemistry and Molecular Biology and Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; Institute for Biotechnology, Bay Zoltán Foundation for Applied Research, Szeged, Hungary; Medicinal Chemistry, Bayer Schering Pharma, Berlin, Germany; ^¶ Common Mechanism Research Berlin, Bayer Schering Pharma, Berlin, Germany; and ^|| Novartis Institutes for Biomedical Research, Vienna, Austria

Activation of vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D₃ (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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The work is supported by grants RET-06/2004 and OTKA NK72730 (to L.N.). L.N. is an International Scholar of the Howard Hughes Medical Institute and holds a Wellcome Trust Senior Research Fellowship in Biomedical Sciences in Central Europe (074021).

² The microarray data presented in this article have been submitted to the Gene Expression Omnibus (GEO) under GEO accession number GSE13762.

³ Address correspondence and reprint requests to Dr. László Nagy, Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, H4012 Debrecen, Hungary. E-mail address: nagyl{at}med.uideb.hu

⁴ Abbreviations used in this paper: DC, dendritic cell; IDC, immature DC; MDC, mature DC; VDR, vitamin D receptor; 1,25-vitD, 1,25-dihydroxyvitamin D₃; 25-vitD, 25-hydroxyvitamin D₃; qPCR, real-time quantitative RT-PCR.

⁵ The online version of this article contains supplemental material.

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