Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Pankaj K. Bhavsar, N. Khorasani, M. Hew, K F Chung

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Abstract

Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone. We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentrationdependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method. SD282 (10-7 M), with dexamethasone (10-6 M), caused a greater inhibition of release of IL-1β, IL-6, macrophage inflammatory protein-1α and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10-9 and 10-10 M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10 -8 and 10-6 M) on LPS-induced IL-8 release in PBMCs from severe asthma. Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK. Copyright

Original languageEnglish
Pages (from-to)750-756
Number of pages7
JournalEuropean Respiratory Journal
Volume35
Issue number4
DOIs
Publication statusPublished - Apr 2010
Externally publishedYes

Keywords

  • Alveolar macrophages
  • Corticosteroid-resistant asthma
  • Cytokines
  • p38 mitogen-activated protein kinase
  • Severe asthma

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