1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype
Abstract
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.
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Vitamin D has an effect on the immune system and can directly affect immune cells.
“It is well known that vitamin D has an effect on immune system and can directly affect immune cells.”
From Vitamin D and Autism Spectrum Disorder: A Literature Review (2016) · cites this paper as [164]
Vitamin D metabolites direct dendritic cells toward a more tolerogenic state.
“For example, vitamin D metabolites have been shown to decrease the secretion of IL-6 and TNF-α [162], enhance the expression of anti-inflammatory cytokines such as interleukin 10 (IL–10) from activated B cells [163], and to direct dendritic cells (DCs) toward a more tolerogenic state [164].”
From Vitamin D and Autism Spectrum Disorder: A Literature Review (2016) · cites this paper as [164]
Cites
Dendritic cells and the control of immunity
Banchereau, J., & Steinman, R. M. (1998) · Nature · doi:10.1038/32588 · Cited by 14,244 · see citing works
Sallusto, F., & Lanzavecchia, A. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.4.1109 · Cited by 5,129 · see citing works
Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells
Nestle, F. O., Alijagic, S., Gilliet, M., Sun, Y., Grabbe, S., Dummer, R., Burg, G., & Schadendorf, D. (1998) · Nature Medicine · doi:10.1038/nm0398-328 · Cited by 2,862 · see citing works
Taking dendritic cells into medicine
Steinman, R., & Banchereau, J. (2007) · Nature · doi:10.1038/nature06175 · Cited by 2,243 · see citing works
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?
Lutz, M. B., & Schuler, G. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02281-0 · Cited by 1,349 · see citing works
Penna, G., & Adorini, L. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.5.2405 · Cited by 1,257 · see citing works
Thurner, B., Haendle, I., Röder, C., Dieckmann, D., Keikavoussi, P., Jonuleit, H., Bender, A., Maczek, C., Schreiner, D., Driesch, P. V. D., et al. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.11.1669 · Cited by 1,226 · see citing works
Dendritic cells in a mature age
Sousa, C. R. E. (2006) · Nature reviews. Immunology · doi:10.1038/nri1845 · Cited by 1,197 · see citing works
Gombart, A. F., Borregaard, N., & Koeffler, H. P. (2005) · The FASEB Journal · doi:10.1096/fj.04-3284com · Cited by 1,132 · see citing works
Iellem, A., Mariani, M., Lang, R., Recalde, H. R., Panina‐Bordignon, P., Sinigaglia, F., & D’Ambrosio, D. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.6.847 · Cited by 915 · see citing works
Tolerogenic dendritic cells and the quest for transplant tolerance
Morelli, A. E., & Thomson, A. W. (2007) · Nature reviews. Immunology · doi:10.1038/nri2132 · Cited by 898 · see citing works
Langerhans cells arise from monocytes in vivo
Ginhoux, F., Tacke, F., Angeli, V., Bogunovic, M., Loubeau, M., Dai, X.-M., Stanley, E. R., Randolph, G. J., & Mérad, M. (2006) · Nature Immunology · doi:10.1038/ni1307 · Cited by 741 · see citing works
Enzymes involved in the activation and inactivation of vitamin D
Prosser, D. E., & JONES, G. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.10.005 · Cited by 659 · see citing works
D’Ambrosio, D., Cippitelli, M., Cocciolo, M., Mazzeo, D., Lucia, P. D., Lang, R., Sinigaglia, F., & Panina‐Bordignon, P. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1050 · Cited by 649 · see citing works
Sigmundsdóttir, H., Pan, J., Debes, G. F., Alt, C., Habtezion, A., Soler, D. F., & Butcher, E. C. (2007) · Nature Immunology · doi:10.1038/ni1433 · Cited by 630 · see citing works
Piemonti, L., Monti, P., Sironi, M., Fraticelli, P., Leone, B. E., Cin, E. D., Allavena, P., & Carlo, V. D. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.9.4443 · Cited by 620 · see citing works
Gregori, S., Casorati, M., Amuchastegui, S., Smiroldo, S., Davalli, A. M., & Adorini, L. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.4.1945 · Cited by 617 · see citing works
Griffin, M. D., Lutz, W. H., Phan, V., Bachman, L. A., McKEAN, D. J., & Kumar, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121172198 · Cited by 600 · see citing works
Control of autoimmune diseases by the vitamin D endocrine system
Adorini, L., & Penna, G. (2008) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0855 · Cited by 558 · see citing works
Dendritic cells: emerging pharmacological targets of immunosuppressive drugs
Hackstein, H., & Thomson, A. W. (2004) · Nature reviews. Immunology · doi:10.1038/nri1256 · Cited by 546 · see citing works
Gregori, S., Giarratana, N., Smiroldo, S., Uskoković, M. R., & Adorini, L. (2002) · Diabetes · doi:10.2337/diabetes.51.5.1367 · Cited by 482 · see citing works
Glucocorticoids Affect Human Dendritic Cell Differentiation and Maturation
Piemonti, L., Monti, P., Allavena, P., Sironi, M., Soldini, L., Leone, B. E., Socci, C., & Carlo, V. D. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.11.6473 · Cited by 466 · see citing works
Hewison, M., Freeman, L., Hughes, S. V., Evans, K. N., Bland, R., Eliopoulos, A. G., Kilby, M. D., Moss, P. A. H., & Chakraverty, R. K. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.11.5382 · Cited by 447 · see citing works
Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer
Hollis, B. W., Kamerud, J., Selvaag, S., Lorenz, J. D., & Napoli, J. L. (1993) · Clinical Chemistry · doi:10.1093/clinchem/39.3.529 · Cited by 432 · see citing works
Penna, G., Roncari, A., Amuchastegui, S., Daniel, K. C., Berti, E., Colonna, M., & Adorini, L. (2005) · Blood · doi:10.1182/blood-2005-05-2044 · Cited by 412 · see citing works
Ehrchen, J. M., Steinmüller, L., Barczyk, K., Tenbrock, K., Nacken, W. K. F., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkötter, C. H., & Roth, J. (2006) · Blood · doi:10.1182/blood-2006-02-001115 · Cited by 407 · see citing works
Penna, G., Amuchastegui, S., Giarratana, N., Daniel, K. C., Vulcano, M., Sozzani, S., & Adorini, L. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.1.145 · Cited by 354 · see citing works
St‐Arnaud, R., Messerlian, S., Moir, J. M., Omdahl, J. L., & Glorieux, F. H. (1997) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1997.12.10.1552 · Cited by 324 · see citing works
Chen, K.-S., & DeLuca, H. F. (1995) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/0167-4781(95)00060-t · Cited by 288 · see citing works
Potent Inhibition of Dendritic Cell Differentiation and Maturation by Vitamin D Analogs
Griffin, M. D., Lutz, W. H., Phan, V., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2490 · Cited by 268 · see citing works
Fritsche, J., Mondal, K., Ehrnsperger, A., Andreesen, R., & Kreutz, M. P. (2003) · Blood · doi:10.1182/blood-2002-11-3521 · Cited by 246 · see citing works
Dunlop, T. W., Vaïsänen, S., Frank, C., Molnár, F., Sinkkonen, L., & Carlberg, C. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.03.060 · Cited by 218 · see citing works
1,25-Dihydroxyvitamin D3 inhibits dendritic cell differentiation and maturation in vitro
Berer, A., Stöckl, J., Majdic, O., Wagner, T., Kollars, M., Lechner, K., Geissler, K. H., & Oehler, L. (2000) · Experimental Hematology · doi:10.1016/s0301-472x(00)00143-0 · Cited by 217 · see citing works
Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands
Adorini, L., Penna, G., Giarratana, N., Roncari, A., Amuchastegui, S., Daniel, K. C., & Uskoković, M. R. (2004) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2004.03.013 · Cited by 205 · see citing works
van Halteren, A. G. S., van Etten, E., de Jong, E. C., Bouillon, R., Roep, B. O., & Mathieu, C. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2119 · Cited by 196 · see citing works
Takeuchi, A., Reddy, G. S., Kobayashi, T., Okano, T., Park, J., & Sharma, S. (1998) · PubMed · Cited by 179 · see citing works
Gauzzi, M. C., Purificato, C., Donato, K., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.1.270 · Cited by 153 · see citing works
Szatmári, I., Gogolák, P., Im, J. S., Dezsö, B., Rajnavölgyi, É., & Nagy, L. (2004) · Immunity · doi:10.1016/j.immuni.2004.06.003 · Cited by 152 · see citing works
Self-citationUnique Regulation of CCL18 Production by Maturing Dendritic Cells
Vulcano, M., Struyf, S., Scapini, P., Cassatella, M. A., Bernasconi, S., Bonecchi, R., Calleri, A., Penna, G., Adorini, L., Luini, W., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3843 · Cited by 151 · see citing works
Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with 125I-labeled tracer
Hollis, B. W., Kamerud, J., Kurkowski, A., Beaulieu, J., & Napoli, J. L. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.4.586 · Cited by 145 · see citing works
Takeuchi, A., Reddy, G. S., Kobayashi, T., Okano, T., Park, J., & Sharma, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.1.209 · Cited by 143 · see citing works
PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism
Szatmári, I., Törőcsik, D., Agostini, M., Nagy, T., Gurnell, M., Barta, E., Chatterjee, K., & Nagy, L. (2007) · Blood · doi:10.1182/blood-2007-06-096222 · Cited by 133 · see citing works
Self-citationThe assessment of circulating 25(OH)D and 1,25(OH)2D: Where we are and where we are going
Hollis, B. W., & Horst, R. L. (2007) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.11.004 · Cited by 128 · see citing works
Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function
Szatmári, I., & Nagy, L. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.160 · Cited by 87 · see citing works
Self-citationMonocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite
Gottfried, E., Rehli, M., Hahn, J. R., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.08.034 · Cited by 85 · see citing works
IREM‐1 is a novel inhibitory receptor expressed by myeloid cells
Álvarez‐Errico, D., Aguilar, H., Kitzig, F., Brckalo, T., Sayós, J., & López‐Botet, M. (2004) · European Journal of Immunology · doi:10.1002/eji.200425433 · Cited by 79 · see citing works
Herdick, M., Steinmeyer, A., & Carlberg, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910000199 · Cited by 74 · see citing works
Self-citationManipulating dendritic cells to induce regulatory T cells
Penna, G., Giarratana, N., Amuchastegui, S., et al. (2005) · Microbes and Infection · doi:10.1016/j.micinf.2005.03.025 · Cited by 38 · see citing works
Gauzzi, M. C., Purificato, C., Conti, L., et al. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0205090 · Cited by 36 · see citing works
Analysis of the 5-lipoxygenase promoter and characterization of a vitamin D receptor binding site
Sorg, B. L., Klan, N., Seuter, S., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2006.04.005 · Cited by 31 · see citing works
Im, H., Craig, T. A., Pittelkow, M. R., & Kumar, R. (2002) · Oncogene · doi:10.1038/sj.onc.1205450 · Cited by 27 · see citing works
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Vitamin D and the immune system
Aranow, C. (2011) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e31821b8755 · Cited by 1,436 · see citing works
Vitamin D and Autism Spectrum Disorder: A Literature Review
Mazahery, H., Camargo, C., Conlon, C., Beck, K., Kruger, M., & Von Hurst, P. (2016) · Nutrients · doi:10.3390/nu8040236 · Cited by 110 · see citing works
- Authors
- Széles, L., Keresztes, G., Töröcsik, D., Balajthy, Z., Krenács, L., Póliska, S., Steinmeyer, A., Zuegel, U., Pruenster, M., Rot, A., & Nagy, L.
- Affiliations
- University of Debrecen (HU)
- Department of Biochemistry and Molecular Biology
- Bay Zoltán Foundation for Applied Research (HU)
- Bayer (Germany) (DE)
- Common Mechanism Research Berlin, Bayer Schering Pharma , Berlin,
- Novartis (Austria) (AT)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-02
- Volume
- 182
- Issue
- 4
- Pages
- 2074-2083
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1638979393
- Cited by
- 234
- References
- 51
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 17 · 2023: 12 · 2022: 16 · 2021: 16 · 2020: 11 · 2019: 17 · 2018: 14 · 2017: 14 · 2016: 7 · 2015: 12 · 2014: 14 · 2013: 18 · 2012: 13
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- 1,25-dihydroxyvitamin D3, vitamin D receptor, dendritic cells, tolerogenic dendritic cells, dendritic cell differentiation, transcriptional regulation, monocyte-derived dendritic cells, CCL22, CYP24A1, gene expression profiling
- MeSH terms
- Calcitriol, Cell Differentiation, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Immune Tolerance, Immunohistochemistry, Phenotype, Transcription, Genetic, Vitamins, Blotting, Western, Receptors, Calcitriol, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Chemokine CCL22
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