PT - JOURNAL ARTICLE AU - Po-Jui Chang AU - Josephine Baker AU - Pankaj K. Bhavsar AU - Mark M. Perry AU - Kian Fan Chung TI - Corticosteroid insensitivity in airway smooth muscle cells of severe asthma and COPD: Modulation by IFN-γ DP - 2012 Sep 01 TA - European Respiratory Journal PG - P1438 VI - 40 IP - Suppl 56 4099 - http://erj.ersjournals.com/content/40/Suppl_56/P1438.short 4100 - http://erj.ersjournals.com/content/40/Suppl_56/P1438.full SO - Eur Respir J2012 Sep 01; 40 AB - Background: Patients with severe asthma or COPD respond poorly to corticosteroids (CS). IFN-γ impairs CS response in airway smooth muscle cells (ASMCs) of healthy subjects. Aims and objectives: Compare cytokine-induced chemokines and CS response in ASMCs of severe asthma or COPD. Investigate the effect of IFN-γ on CS response. Methods: ASMCs of healthy subjects (12), non-severe (NSA; 10) and severe asthma (SA; 10), smokers (8) and COPD (8), were obtained via endobronchial biopsy. At passage 4-5, cells were pretreated with dexamethasone (Dex; 10-10-10-6 M; 2 hr) and stimulated with TNF-α/IFN-γ (10 ng/mL each; 24 hr). CCL11 and CXCL8 release and mRNA were assessed by ELISA and qRT-PCR, p65 NF-κB promoter recruitment by ChIP, and p38 MAPK activity by Western Blot. Results: Baseline and TNFα-induced CCL11 release/mRNA were increased in NSA, and CXCL8 increased at baseline in smokers and COPD. Dex suppression of induced chemokines was impaired in SA, smokers and COPD. IFN-γ inhibited i) induced CCL11 and CXCL8; ii) p65 recruitment to chemokine promoters, and iii) Dex suppression of induced chemokines in the healthy. In SA, IFN-γ further reduced suppression of only CXCL8. Paradoxically, IFN-γ improved the suppressive effect of Dex on CXCL8 in smokers and COPD. p38 MAPK activity was raised in SA, and inhibition of p38 restored corticosteroid sensitivity. However, IFN-γ did not modulate induced p38 activity. Conclusions: ASMCs of SA, smokers and COPD display CS insensitivity. IFN-γ impairs the suppressive effect of Dex on CXCL8 in the healthy and asthmatics but improves it in smokers and COPD, suggesting differential mechanisms underlying CS insensitivity in SA and smokers/COPD.