TY - JOUR T1 - p38 MAP Kinase-γ Inhibition by Long-acting β2 Adrenergic Agonists Reversed Steroid Insensitivity in Severe Asthma JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.071993 SP - mol.111.071993 AU - Nicolas Mercado AU - Yasuo To AU - Yoshiki Kobayashi AU - Ian M Adcock AU - Peter J Barnes AU - Kazuhiro Ito Y1 - 2011/09/14 UR - http://molpharm.aspetjournals.org/content/early/2011/09/14/mol.111.071993.abstract N2 - Corticosteroid insensitivity (CI) is a major barrier to treating severe asthma. Despite intensive research, the molecular mechanism of CI remains uncertain. The aim of this study was to determine abnormality in corticosteroid action in severe asthma, and to identify the molecular mechanism of the long-acting β2-adrenergic agonists (LABAs), formoterol and salmeterol, on restoration of corticosteroid sensitivity in severe asthma in vitro.Peripheral blood mononuclear cells (PBMCs) were obtained from 16 subjects with severe corticosteroid-insensitive asthma, 6 subjects from mild corticosteroid-sensitive asthma and 11 healthy volunteers. Corticosteroid (dexamethasone) sensitivity was determined on TNF-α induced IL-8 production. Glucocorticoid receptor (GR) phosphorylation and kinase phosphorylation were evaluated by immunoprecipitation-western blotting and kinase phosphorylation array in IL-2/IL-4-treated corticosteroid insensitive model in PBMCs. In vitro corticosteroid sensitivity on TNF-α induced IL-8 production was significantly lower in severe asthma than those of healthy volunteers and mild asthmatics. This CI seen in severe asthma was associated with reduced GR nuclear translocation and also with hyper-phosphorylation of GR, which were reversed by LABAs. In IL-2/IL-4- treated PBMCs, LABAs inhibited phosphorylation of JNK and p38MAPK-γ as well as GR phosphorylation. In addition, cells with p38MAPK-γ knock-down by RNA interference did not develop CI in the presence of IL-2/IL-4. Furthermore, p38MAPK-γ protein expression was up-regulated in PBMCs from some patients with severe asthma. In conclusion, p38 MAPK-γ activation impairs corticosteroid action and p38 MAPK-γ inhibition by LABAs has potential for the treatment of severe asthma. ER -