Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma.

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

doi:10.1371/journal.pone.0041582

Abstract

BackgroundSevere 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.Methodology/Principal FindingsCorticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α 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 p38α/β 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.Conclusions/Significancep38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.

Highlights

Most patients with asthma have mild to moderate forms of the disease and are well controlled by corticosteroids or a combination of corticosteroids and long-acting b2-adrenoreceptors agonists (LABA)
In the present study we showed that a p38MAPK inhibitor (SB203580) preferentially restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from a subpopulation of severe asthma that were characterized by increased ex-vivo corticosteroid insensitivity, decreased glucocorticoid receptor (GR) nuclear translocation and clinically by a tendency for reduced lung function and higher use of oral corticosteroids
Basal levels of IL-8 in PBMCs after overnight incubation were similar between patient groups (Table 2)

Summary

Introduction

Most patients with asthma have mild to moderate forms of the disease and are well controlled by corticosteroids or a combination of corticosteroids and long-acting b2-adrenoreceptors agonists (LABA). Between 5–10% of patients remain symptomatic despite treatment with high doses of corticosteroids [1,2]. This group of patients account for about 50% of total health care cost in asthma [3]. It is important to investigate both clinical and molecular features of corticosteroid resistance in severe asthma in order to better understand the complexity of the disease and identify any specific treatment. 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

Methods

Results

Conclusion