title: Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.
abstract: 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.
authors.affiliation: Surgical Research Laboratories, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Kambis
authors.initials: K
authors.lastname: Sadeghi
authors.forename: Barbara
authors.initials: B
authors.lastname: Wessner
authors.forename: Ute
authors.initials: U
authors.lastname: Laggner
authors.forename: Martin
authors.initials: M
authors.lastname: Ploder
authors.forename: Dietmar
authors.initials: D
authors.lastname: Tamandl
authors.forename: Josef
authors.initials: J
authors.lastname: Friedl
authors.forename: Ullrich
authors.initials: U
authors.lastname: Zügel
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Arnold
authors.initials: A
authors.lastname: Pollak
authors.forename: Erich
authors.initials: E
authors.lastname: Roth
authors.forename: George
authors.initials: G
authors.lastname: Boltz-Nitulescu
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000276:immunology / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C410228:ZK159222; D002762:Cholecalciferol; C009900:lipoteichoic acid; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D002117:Calcitriol