Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns
Open accessAbstract
Toll-like receptors (TLR) represent an ancient front-line defence system that enables the host organism to sense the presence of microbial components within minutes. As inducers of inflammation, TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation. We report here that vitamin D3 [1alpha,25-dihydroxycholecalciferol, 1,25(OH)(2)D3] suppresses the expression of TLR2 and TLR4 protein and mRNA in human monocytes in a time- and dose-dependent fashion. Despite 1,25(OH)(2)D3-induced up-regulation of CD14, challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired TNF-alpha and procoagulatory tissue factor (CD142) production, emphasizing the critical role of TLR in the induction of inflammation. Moreover, reduced TLR levels in 1,25(OH)(2)D3-treated phagocytes were accompanied by impaired NF-kappaB/RelA translocation to the nucleus and by reduced p38 and p42/44 (extracellular signal-regulated kinase 1/2) phosphorylation upon TLR-ligand engagement. Both TLR down-regulation and CD14 up-regulation were substantially inhibited by the vitamin D receptor (VDR) antagonist ZK 159222, indicating that the immunomodulatory effect of 1,25(OH)(2)D3 on innate immunity receptors requires VDR transcription factor activation. Our data provide strong evidence that 1,25(OH)(2)D3 primes monocytes to respond less effectively to bacterial cell wall components in a VDR-dependent mechanism, most likely due to decreased levels of TLR2 and TLR4.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FoxO proteins regulate genes involved in energy homeostasis, cell survival, and inflammatory responses including NF-kB.
“FoxO proteins are transcription factors which regulate the expression of genes involved in energy homeostasis, cell survival and inflammatory responses including NF-kB (274 -278) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [277]
Cites
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A. J. (1997) · Nature · doi:10.1038/41131 · Cited by 6,137 · see citing works
LPS induction of gene expression in human monocytes.
Guha, M., & Mackman, N. (2001) · Cellular Signalling · doi:10.1016/s0898-6568(00)00149-2 · Cited by 2,441 · see citing works
Disseminated Intravascular Coagulation
Levi, M. M., & Cate, H. T. (1999) · New England Journal of Medicine · doi:10.1056/nejm199908193410807 · Cited by 2,027 · see citing works
Hornung, V., Rothenfußer, S., Britsch, S., Krug, A., Jahrsdörfer, B., Giese, T., Endres, S., & Hartmann, G. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.9.4531 · Cited by 1,927 · see citing works
Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction
Chow, J. C., Young, D. W., Golenbock, D. T., Christ, W. J., & Gusovsky, F. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.16.10689 · Cited by 1,924 · see citing works
MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.
Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C.-Q., Ghosh, S., & Janeway, C. (1998) · Molecules and Cells · doi:10.1016/s1097-2765(00)80136-7 · Cited by 1,783 · see citing works
Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2
Schwandner, R., Dziarski, R., Wesche, H., Rothe, M., & Kirschning, C. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17406 · Cited by 1,704 · see citing works
Bevilacqua, M. P., Pober, J. S., Majeau, G. R., Fiers, W. C., Cotran, R. S., & Gimbrone, M. A. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.12.4533 · Cited by 1,059 · see citing works
1,25-Dihydroxyvitamin D 3 Receptors in Human Leukocytes
Provvedini, D. M., Cd, T., Deftos, L. J., & Manolagas, S. C. (1983) · Science · doi:10.1126/science.6310748 · Cited by 1,035 · see citing works
Cloning and expression of full-length cDNA encoding human vitamin D receptor.
Baker, A. R., McDonnell, D. P., Hughes, M., Crisp, T. M., Mangelsdorf, D. J., Haussler, M. R., Pike, J. W., Shine, J., & O’Malley, B. W. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.10.3294 · Cited by 959 · see citing works
Magnetic relaxation switches capable of sensing molecular interactions
Pérez, J. M. S., Josephson, L., O'Loughlin, T., Högemann, D., & Weissleder, R. (2002) · Nature Biotechnology · doi:10.1038/nbt720 · Cited by 889 · see citing works
Activation of Toll-Like Receptor-2 by Glycosylphosphatidylinositol Anchors from a Protozoan Parasite
Campos, M. A., de Almeida, I. C., Takeuchi, O., Akira, S., Valente, E. P., Procópio, D. O., Travassos, L. R., Smith, J. A., Golenbock, D. T., & Gazzinelli, R. T. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.1.416 · Cited by 587 · see citing works
Krutzik, P. O., & Nolan, G. P. (2003) · Cytometry Part A · doi:10.1002/cyto.a.10072 · Cited by 564 · see citing works
Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation
Hausmann, M., Kießling, S., Mestermann, S., Webb, G. R., Spöttl, T., Andus, T., Schölmerich, J., Herfarth, H. H., Ray, K., Falk, W., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.33662 · Cited by 488 · see citing works
Eriksson, U., Ricci, R., Hunziker, L., Kurrer, M. O., Oudit, G. Y., Watts, T. H., Sonderegger, I., Bachmaier, K., Kopf, M., & Penninger, J. M. (2003) · Nature Medicine · doi:10.1038/nm960 · Cited by 405 · see citing works
Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells
Chuang, T., & Ulevitch, R. J. (2001) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00289-x · Cited by 398 · see citing works
Mackman, N., Brand, K., & Edgington, T. S. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.174.6.1517 · Cited by 377 · see citing works
Simultaneous measurement of multiple active kinase states using polychromatic flow cytometry
Perez, O. D., & Nolan, G. P. (2002) · Nature Biotechnology · doi:10.1038/nbt0202-155 · Cited by 279 · see citing works
Monocyte antigen CD14 is a phospholipid anchored membrane protein
Simmons, D., Tan, S., Tenen, D. G., Nicholson-Weller, A., & Seed, B. (1989) · Blood · doi:10.1182/blood.v73.1.284.284 · Cited by 266 · see citing works
Zhu, Y., Mahon, B. D., Froicu, M., & Cantorna, M. T. (2004) · European Journal of Immunology · doi:10.1002/eji.200425491 · Cited by 260 · see citing works
Friedl, J., Puhlmann, M., Bartlett, D. L., Libutti, S. K., Turner, E. N., Gnant, M., & Alexander, H. R. (2002) · Blood · doi:10.1182/blood.v100.4.1334.h81602001334_1334_1339 · Cited by 177 · see citing works
Self-citationCutting Edge: All-trans Retinoic Acid Down-Regulates TLR2 Expression and Function
Liu, P. T., Krutzik, S. R., Kim, J., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2467 · Cited by 175 · see citing works
Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1
Manukyan, M., Triantafilou, K., Triantafilou, M., Mackie, A. R., Nilsen, N. J., Espevik, T., Wiesmüller, K., Ulmer, A. J., & Heine, H. (2005) · European Journal of Immunology · doi:10.1002/eji.200425336 · Cited by 152 · see citing works
Zhang, D. E., Hetherington, C. J., Gonzalez, D. A., et al. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.7.3276 · Cited by 109 · see citing works
Bench-to-bedside review: Toll-like receptors and their role in septic shock.
Opal, S. M., & Huber, C. E. (2002) · Critical Care · doi:10.1186/cc1471 · Cited by 102 · see citing works
1α,25‐Dihydroxyvitamin D3 decreases DNA binding of nuclear factor‐κB in human fibroblasts
Harant, H., Wolff, B., & Lindley, I. J. D. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)01153-3 · Cited by 100 · 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-citationBoth membrane‐bound and soluble forms of CD14 bind to Gram‐negative bacteria
Jack, R. S., Grunwald, U., Stelter, F., et al. (1995) · European Journal of Immunology · doi:10.1002/eji.1830250545 · Cited by 64 · see citing works
Regulation of TNF-α by 1α,25-dihydroxyvitamin D3 in human macrophages from CAPD patients
Cohen, M., Douvdevani, A., Chaimovitz, C., & Shany, S. (2001) · Kidney International · doi:10.1046/j.1523-1755.2001.00467.x · Cited by 63 · see citing works
Boltz‐Nitulescu, G., Wiilheim, M., Spittler, A., et al. (1995) · Journal of Leukocyte Biology · doi:10.1002/jlb.58.2.256 · Cited by 62 · see citing works
Self-citationSpittler, A., Willheim, M., Leutmezer, F., et al. (1997) · Immunology · doi:10.1046/j.1365-2567.1997.00148.x · Cited by 53 · see citing works
Self-citationAoshima, K., Suga, Y., Yamazaki, M., et al. (2001) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1615681 · Cited by 47 · see citing works
Giovannini, L., Panichi, V., MIGLIORI, M., et al. (2001) · Transplantation Proceedings · doi:10.1016/s0041-1345(01)02023-1 · Cited by 28 · see citing works
Takahashi, K., Horiuchi, H., Ohta, T., et al. (2002) · Immunopharmacology and Immunotoxicology · doi:10.1081/iph-120003399 · Cited by 25 · see citing works
Disseminated Intravascular Coagulation
Schmaier, A. H. (1999) · New England Journal of Medicine · doi:10.1056/nejm199912163412515 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dietary factors and low-grade inflammation in relation to overweight and obesity
Calder, P. C., Ahluwalia, N., Brouns, F., Buetler, T., Clement, K., Cunningham, K., Esposito, K., Jönsson, L. S., Kolb, H., Lansink, M., et al. (2011) · British Journal of Nutrition · doi:10.1017/s0007114511005460 · Cited by 1,098 · see citing works
Vitamin D3: a helpful immuno-modulator: Vitamin D3 as immuno-modulator
Di Rosa, M., Malaguarnera, M., Nicoletti, F., & Malaguarnera, L. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03482.x · Cited by 447 · see citing works
Inflammation and vitamin D: The infection connection
Mangin, M., Sinha, R., & Fincher, K. (2014) · Inflammation Research · doi:10.1007/s00011-014-0755-z · Cited by 274 · see citing works
Vitamin D Endocrine System and the Immune Response in Rheumatic Diseases
Cutolo, M., Plebani, M., Shoenfeld, Y., Adorini, L., & Tincani, A. (2011) · Vitamins & Hormones · doi:10.1016/b978-0-12-386960-9.00014-9 · Cited by 86 · see citing works
Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions
Walker, D., & Lue, L.-F. (2007) · Current Neuropharmacology · doi:10.2174/157015907782793667 · Cited by 66 · see citing works
- Authors
- Sadeghi, K., Wessner, B., Laggner, U., Ploder, M., Tamandl, D., Friedl, J., Zügel, U., Steinmeyer, A., Pollak, A., Roth, E., Boltz‐Nitulescu, G., & Spittler, A.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Spittler, Andreas
- ORCID
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2006-02
- Volume
- 36
- Issue
- 2
- Pages
- 361-370
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1985558958
- Cited by
- 513
- References
- 35
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 13 · 2023: 27 · 2022: 29 · 2021: 41 · 2020: 27 · 2019: 23 · 2018: 28 · 2017: 26 · 2016: 27 · 2015: 40 · 2014: 31 · 2013: 30 · 2012: 49
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- vitamin D3, 1,25-dihydroxyvitamin D3, vitamin D receptor, TLR2, TLR4, monocytes, innate immunity, CD14, lipopolysaccharide, lipoteichoic acid, TNF-α, tissue factor, MAPK signaling, immunomodulation, bacterial cell wall components
- MeSH terms
- Calcitriol, Cells, Cultured, Cholecalciferol, Dose-Response Relationship, Drug, Humans, Inflammation, Lipopolysaccharides, Macrophage Activation, Monocytes, Phosphorylation, Teichoic Acids, Signal Transduction, Down-Regulation, Up-Regulation, Receptors, Calcitriol, Lipopolysaccharide Receptors, Mitogen-Activated Protein Kinase 1, Active Transport, Cell Nucleus, p38 Mitogen-Activated Protein Kinases, Toll-Like Receptor 2, Toll-Like Receptor 4, Transcription Factor RelA
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review