title: Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD.
abstract: 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.
  
  
  CONCLUSIONS
  p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
authors: Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK.
authors: Nadia
authors: N
authors: Khorasani
authors: Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK.
authors: Josephine
authors: J
authors: Baker
authors: GlaxoSmithKline, Uxbridge, UK.
authors: Malcolm
authors: M
authors: Johnson
authors: Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK.
authors: Kian Fan
authors: KF
authors: Chung
authors: Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK.
authors: Pankaj K
authors: PK
authors: Bhavsar
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D000305:Adrenal Cortex Hormones; C508606:CXCL8 protein, human; D003521:Cyclopropanes; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011965:Receptors, Glucocorticoid; D012694:Serine; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases
keywords: glucocorticoid receptor; p38 mitogen-activated protein kinase