title: Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma.
abstract: BACKGROUND
  Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.
  
  
  OBJECTIVE
  We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies.
  
  
  RESULTS
  GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10(-7) M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α-induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α-induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA.
  
  
  CONCLUSIONS
  Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB-dependent gene promoters, may underlie CS insensitivity of severe asthma.
authors.affiliation: 1 Experimental Studies, Airway Disease Section, and.
authors.forename: Po-Jui
authors.initials: PJ
authors.lastname: Chang
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Nooreen
authors.initials: N
authors.lastname: Shaikh
authors.forename: Josephine
authors.initials: J
authors.lastname: Baker
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
mesh_terms: D000305:Adrenal Cortex Hormones / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000305:Adrenal Cortex Hormones; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha
keywords: airway smooth muscle; asthma; corticosteroid insensitivity; glucocorticoid receptor; nuclear translocation