Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns
| Autor: | George Boltz-Nitulescu, Andreas Steinmeyer, Josef Friedl, Kambis Sadeghi, Andreas Spittler, Dietmar Tamandl, Erich Roth, Barbara Wessner, Martin Ploder, Ullrich Zügel, Arnold Pollak, Ute Laggner |
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| Rok vydání: | 2006 |
| Předmět: |
Lipopolysaccharides
CD14 Immunology Active Transport Cell Nucleus Lipopolysaccharide Receptors Down-Regulation Biology Calcitriol receptor p38 Mitogen-Activated Protein Kinases Monocytes Calcitriol medicine Immunology and Allergy Humans Phosphorylation Receptor Cells Cultured Cholecalciferol Inflammation Mitogen-Activated Protein Kinase 1 Dose-Response Relationship Drug Monocyte Pathogen-associated molecular pattern Transcription Factor RelA Macrophage Activation Toll-Like Receptor 2 Up-Regulation Teichoic Acids Toll-Like Receptor 4 TLR2 medicine.anatomical_structure TLR4 Receptors Calcitriol Signal transduction Signal Transduction |
| Zdroj: | University of Vienna-u:cris |
| ISSN: | 0014-2980 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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