title: Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.
abstract: BACKGROUND
  Vitamin D is known for its anti-inflammatory effects.
  
  
  OBJECTIVE
  Vitamin D regulation of responses in patients with steroid-resistant (SR) versus steroid-sensitive (SS) asthma has not been studied.
  
  
  METHODS
  Peripheral blood cells from 11 patients with SR asthma and 8 patients with SS asthma were preincubated with 1,25-dihydroxyvitamin D (1,25[OH]2D [VitD]), followed by dexamethasone (DEX) treatment and LPS stimulation. LPS-induced phosphorylated p38 mitogen-activated protein kinase (p-p38) in monocytes was examined by means of flow cytometry. Mitogen-activated protein kinase phosphatase-1 (MKP-1) mRNA expression, which inhibits p-p38, was analyzed by means of real-time PCR. Glucocorticoid receptor (GR) binding and histone H4 acetylation in the glucocorticoid response element of the MKP-1 promoter in monocytes were analyzed by means of chromatin immunoprecipitation.
  
  
  RESULTS
  DEX significantly inhibited LPS-induced p-p38 in monocytes from patients with SS asthma but not those from patients with SR asthma (P < .01). VitD inhibited LPS-induced p-p38 in monocytes from both patient groups (P < .01) but enhanced DEX suppression of LPS-induced p-p38 only in monocytes from patients with SS asthma (P < .01). VitD induced MKP-1 expression and enhanced DEX induction of MKP-1 in both patients with SS asthma and patients with SR asthma. VitD/DEX-induced MKP-1 mRNA levels remained significantly lower in monocytes from patients with SR asthma (P < .05). DEX-stimulated recruitment of GR and histone H4 acetylation at the glucocorticoid response element 4.6 kbp upstream of the MKP-1 gene were significantly lower in monocytes from patients with SR asthma compared with those from patients with SS asthma. VitD pretreatment enhanced DEX-induced GR binding and histone acetylation in monocytes from both patient groups. However, GR binding and histone H4 acetylation remained significantly lower in monocytes from patients with SR asthma.
  
  
  CONCLUSIONS
  VitD demonstrated anti-inflammatory and corticosteroid-enhancing effects in monocytes of patients with SR asthma and patients with SS asthma. However, the responses to corticosteroids in patients with SR asthma remained significantly lower than those in patients with SS asthma.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Pediatrics, University of Colorado Denver, Aurora, Colo.
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo. Electronic address: golevae@njhealth.org.
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
mesh_terms: D000107:Acetylation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D004351:Drug Resistance; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012129:Respiratory Function Tests; D020218:Response Elements; D014807:Vitamin D / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D006657:Histones; D015850:Interleukin-6; D011965:Receptors, Glucocorticoid; D014807:Vitamin D; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: Asthma; corticosteroids; steroid resistance; vitamin D