Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD
Authors Khorasani N, Baker J, Johnson M, Chung KF, Bhavsar P
Received 7 August 2014
Accepted for publication 10 October 2014
Published 4 February 2015 Volume 2015:10(1) Pages 283—291
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 4
Editor who approved publication: Dr Richard Russell
Nadia Khorasani,1 Josephine Baker,1 Malcolm Johnson,2 Kian Fan Chung,1 Pankaj K Bhavsar1
1Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK; 2GlaxoSmithKline, Uxbridge, UK
Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructive pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients with COPD.
Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10–10–10–6 M), with dexamethasone (10–10–10–6 M), or with both. Phosphorylated glucocorticoid receptor (GR) was measured by Western blot.
Results: Baseline (P<0.01) and LPS-induced (P<0.05) CXCL8 release was greater in PBMCs from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone (10–6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increased in PBMCs of COPD. GW856553 (10–9 and 10–10 M) synergistically increased the inhibitory effect of dexamethasone (10–8 and 10–6 M) on LPS-induced CXCL8 release in COPD. Similar results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.
Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
Keywords: glucocorticoid receptor, p38 mitogen-activated protein kinase
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