title: Down-regulation of IL-8 by high-dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1.
abstract: OBJECTIVE
  There is current interest in vitamin D as a potential anti-inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up-regulates the anti-inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL-8. IL-8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down-regulate IL-8 production in CF macrophages.
  
  
  METHODS
  CF and healthy monocyte-derived macrophages (MDM) were treated with two vitamin D metabolites, 25-hydroxyvitamin D3 (25OHD3 ) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), or paricalcitol, synthetic analogue of 1,25(OH)2 D3 . 25OHD3 was tested at doses of 25-150 nM, whereas 1,25(OH)2 D3 and paricalcitol at doses of up to 100 nM. IL-8 was stimulated by bacterial virulence factors. As potential anti-inflammatory mechanism of vitamin D metabolites, we assessed up-regulation of DUSP1.
  
  
  RESULTS
  MDM from patients with CF and some healthy donors showed excessive production of stimulated IL-8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down-regulated stimulated IL-8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3 , or >1 nM for 1,25(OH)2 D3 and paricalcitol). The magnitude of IL-8 down-regulation by vitamin D metabolites or paricalcitol was moderate (∼30% vs. >70% by low-dose dexamethasone). Transcriptional up-regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL-8 down-regulation.
  
  
  CONCLUSIONS
  Vitamin D metabolites and their analogues moderately down-regulate IL-8 in hyperinflammatory macrophages, including those from CF. This down-regulation appears to go through DUSP1-independent mechanisms.
authors.affiliation: Translational Research in Respiratory Diseases, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Dauletbaev
authors.affiliation: Translational Research in Respiratory Diseases, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Herscovitch
authors.affiliation: Translational Research in Respiratory Diseases, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Das
authors.affiliation: Translational Research in Respiratory Diseases, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Respiratory Medicine, Montreal Chest Institute, Montreal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Bernier
authors.affiliation: Division of Respiratory Medicine, Montreal Chest Institute, Montreal, QC, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Matouk
authors.affiliation: Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Bérubé
authors.affiliation: Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Translational Research in Respiratory Diseases, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.|Division of Respiratory Medicine, Montreal Children's Hospital, Montreal, QC, Canada.
authors.forename: L C
authors.initials: LC
authors.lastname: Lands
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000328:Adult; D002112:Calcifediol / Q000097:blood / Q000494:pharmacology*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism*; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics; D055815:Young Adult
chemical_list: D004872:Ergocalciferols; D016209:Interleukin-8; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C084656:paricalcitol; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D002112:Calcifediol