title: Vitamin D [1,25(OH)2D3] Differentially Regulates Human Innate Cytokine Responses to Bacterial versus Viral Pattern Recognition Receptor Stimuli.
abstract: Vitamin D plays multiple roles in regulation of protective and maladaptive immunity. Although epidemiologic studies link poor in vivo 25(OH)D status to increased viral respiratory infections, we poorly understand how vitamin D affects viral pattern recognition receptor (PRR)-driven cytokine production. In this study, we hypothesized that the biologically active metabolite of vitamin D, 1,25(OH)2D3, inhibits human proinflammatory and anti-inflammatory innate cytokine responses stimulated by representative bacterial or viral PRR ligands. Fresh PBMCs or CD14(+) monocytes were stimulated with TLR4, TLR7/8-selective ligands, or respiratory syncytial virus (RSV) ± 1,25(OH)2D3. Proinflammatory and anti-inflammatory responses resulting from TLR4 stimulation were inhibited ∼50% in the presence of 1,25(OH)2D3. Conversely, its usage at physiologic through pharmacologic concentrations inhibited neither proinflammatory nor anti-inflammatory responses evoked by viral PRR ligands or infectious RSV. This differential responsiveness was attributed to the finding that TLR7/8, but not TLR4, stimulation markedly inhibited vitamin D receptor mRNA and protein expression, selectively reducing the sensitivity of viral PRR responses to modulation. 1,25(OH)2D3 also enhanced expression of IkBa, a potent negative regulator of NF-κB and cytokine production, in TLR4-stimulated monocytes while not doing so upon TLR7/8 stimulation. Thus, 1,25(OH)2D3 inhibits both proinflammatory and a broad panel of anti-inflammatory responses elicited by TLR4 stimulation, arguing that the common view of it as an anti-inflammatory immune response modifier is an oversimplification. In viral responses, it consistently fails to modify TLR7/8- or RSV-stimulated innate cytokine production, even at supraphysiologic concentrations. Collectively, the data call into question the rationale for increasingly widespread self-medication with vitamin D supplements.
authors.affiliation: Department of Immunology, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada; and.
authors.forename: Natascha
authors.initials: N
authors.lastname: Fitch
authors.affiliation: Department of Immunology, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada; and Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors.forename: Allan B
authors.initials: AB
authors.lastname: Becker
authors.affiliation: Department of Immunology, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada; and Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada kent.hayglass@umanitoba.ca.
authors.forename: Kent T
authors.initials: KT
authors.lastname: HayGlass
mesh_terms: D000293:Adolescent; D000328:Adult; D001419:Bacteria / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D014780:Viruses / Q000276:immunology*; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; D051192:Receptors, Pattern Recognition; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014807:Vitamin D; D065668:Vitamin D3 24-Hydroxylase