Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma.
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 concentration-dependent 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-1beta, IL-6, macrophage inflammatory protein-1alpha 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.
Section of Airways Disease, National Heart & Lung Institute, Imperial College & Royal Brompton and Harefield NHS Trust Hospital, London, UK.
P
P
Bhavsar
N
N
Khorasani
M
M
Hew
M
M
Johnson
K F
KF
Chung
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D012720:Severity of Illness Index; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000305:Adrenal Cortex Hormones; C515429:CCL3 protein, human; D054405:Chemokine CCL3; D016207:Cytokines; D004791:Enzyme Inhibitors; C508609:IL10 protein, human; C508600:IL6 protein, human; D007211:Indoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C514526:indole-5-carboxamide; D016753:Interleukin-10; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases