by Nicolas Mercado, Amir Hakim, Yoshiki Kobayashi, Sally Meah, Omar S. Usmani, Kian Fan Chung, Peter J. Barnes, Kazuhiro Ito

Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders.

Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-a induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC₅₀ values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r?=?-0.65; p<0.0005) and with decreased FEV₁ (% predicted) (r?=?0.6; p<0.0005). A p38a/ß inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV₁ and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s.

p38MAPKa/ß is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKa/ß inhibitor in the future.