title: Influence of 1,25-dihydroxy vitamin D3 on TLR4-induced activation of antigen presenting cells is dependent on the order of receptor engagement.
abstract: The vitamin D metabolite, 1,25-(OH)₂D₃, binds the vitamin D receptor (VDR) to exert its regulatory effects at the transcription level. VDR is expressed in professional antigen-presenting cells (pAPCs), such as macrophages (Mø) and dendritic cells (DCs). We show for the first time that the 24-hydroxylase enzyme is activated in bone marrow-derived dendritic cell (BMDC), due to 1,25(OH)₂D₃ stimulation which resulted in the induction of its gene, CYP24A1. Furthermore, we provide evidence that the influence of 1,25-(OH)₂D₃ on TLR-4-L-induced activation of pAPC is dependent on the order of VDR and TLR-4 engagement. Thus, pre-treatment of pAPC with 1,25-(OH)₂D₃ partially inhibited LPS-induced nitric oxide (NO) production. However, these inhibitory effects were not observed when LPS and 1,25-(OH)₂D₃ were added simultaneously or when LPS preceded 1,25-(OH)₂D₃. Moreover, we found that 1,25-(OH)₂D₃ pre-treatment of pAPCs did not cause general suppression since it interfered with NO levels but not with the cytokines IL-6 or TNF-α. Consequently, engagement of VDR by 1,25-(OH)₂D₃ can partially interfere with TLR-4-L-induced activation of pAPCs only when it occurs before TLR-4 stimulation.
authors.affiliation: Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Vandana
authors.initials: V
authors.lastname: Gambhir
authors.forename: Julia
authors.initials: J
authors.lastname: Kim
authors.forename: Sarah
authors.initials: S
authors.lastname: Siddiqui
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: Valarie
authors.initials: V
authors.lastname: Byford
authors.forename: Elaine O
authors.initials: EO
authors.lastname: Petrof
authors.forename: Glenville
authors.initials: G
authors.lastname: Jones
authors.forename: Sameh
authors.initials: S
authors.lastname: Basta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D007109:Immunity / Q000187:drug effects* / Q000502:physiology; D056747:Immunomodulation; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D013250:Steroid Hydroxylases; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase