Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma

J Allergy Clin Immunol. 2012 Oct;130(4):877-85.e5. doi: 10.1016/j.jaci.2012.07.017. Epub 2012 Sep 1.


Background: Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.

Objective: We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.

Methods: ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.

Results: CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.

Conclusions: ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asthma / drug therapy*
  • Asthma / immunology
  • Bronchi / drug effects*
  • Bronchi / immunology
  • Cells, Cultured
  • Chemokines / genetics*
  • Chemokines / metabolism
  • Dexamethasone / pharmacology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism
  • Promoter Regions, Genetic
  • Transcription Factor RelA / physiology


  • Chemokines
  • Transcription Factor RelA
  • Dexamethasone
  • Mitogen-Activated Protein Kinases