Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD

Int J Chron Obstruct Pulmon Dis. 2015 Feb 4;10:283-91. doi: 10.2147/COPD.S72403. eCollection 2015.

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.

Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.

Keywords: glucocorticoid receptor; p38 mitogen-activated protein kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Aged
  • Case-Control Studies
  • Cells, Cultured
  • Cyclopropanes / pharmacology*
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Female
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / enzymology
  • Leukocytes, Mononuclear / immunology
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Pulmonary Disease, Chronic Obstructive / blood
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / enzymology
  • Pulmonary Disease, Chronic Obstructive / immunology
  • Pyridines / pharmacology*
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism
  • Serine
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide
  • Adrenal Cortex Hormones
  • CXCL8 protein, human
  • Cyclopropanes
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Pyridines
  • Receptors, Glucocorticoid
  • Serine
  • Dexamethasone
  • p38 Mitogen-Activated Protein Kinases