Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma

Background 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. Methodology/Principal Findings Corticosteroid 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/Significance p38MAPKα/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.

[1]  C. Rossios,et al.  Corticosteroid insensitivity is reversed by formoterol via phosphoinositide‐3‐kinase inhibition , 2012, British journal of pharmacology.

[2]  Mary Ellen Kitler,et al.  European Respiratory Society , 2005, International Journal of Pharmaceutical Medicine.

[3]  P. Barnes,et al.  Defects of Protein Phosphatase 2A Causes Corticosteroid Insensitivity in Severe Asthma , 2011, PloS one.

[4]  I. Adcock,et al.  p38 Mitogen-Activated Protein Kinase-γ Inhibition by Long-Acting β2 Adrenergic Agonists Reversed Steroid Insensitivity in Severe Asthma , 2011, Molecular Pharmacology.

[5]  K. Chung,et al.  p38 mitogen-activated protein kinase pathways in asthma and COPD. , 2011, Chest.

[6]  I. Adcock,et al.  Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. , 2010, American journal of respiratory and critical care medicine.

[7]  E. Israel,et al.  Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma , 2010, Respiratory research.

[8]  Dave Singh,et al.  A Randomized, Placebo‐Controlled Study of the Effects of the p38 MAPK Inhibitor SB‐681323 on Blood Biomarkers of Inflammation in COPD Patients , 2010, Journal of clinical pharmacology.

[9]  K. Chung,et al.  Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma , 2009, European Respiratory Journal.

[10]  N. Damjanov,et al.  Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. , 2009, Arthritis and rheumatism.

[11]  T. Cheng,et al.  Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. , 2009, Arthritis and rheumatism.

[12]  D. Leung,et al.  IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance. , 2009, American journal of respiratory cell and molecular biology.

[13]  I. Adcock,et al.  Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma , 2008, Thorax.

[14]  I. Pavord,et al.  Increased sputum and bronchial biopsy IL-13 expression in severe asthma. , 2008, The Journal of allergy and clinical immunology.

[15]  R. Polosa,et al.  An overview of chronic severe asthma , 2008, Internal medicine journal.

[16]  W. Busse,et al.  Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. , 2008, Journal of applied physiology.

[17]  I. Pavord,et al.  Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. , 2007, Chest.

[18]  I. Adcock,et al.  Impact of protein acetylation in inflammatory lung diseases. , 2007, Pharmacology & therapeutics.

[19]  M. Strand,et al.  ATF2 impairs glucocorticoid receptor-mediated transactivation in human CD8+ T cells. , 2007, Blood.

[20]  W. Busse,et al.  Severe asthma in adults: what are the important questions? , 2007, The Journal of allergy and clinical immunology.

[21]  N. Thomson,et al.  Systemic sensitivity to corticosteroids in smokers with asthma , 2006, European Respiratory Journal.

[22]  G. Rossi,et al.  High serum levels of tumour necrosis factor‐α and interleukin‐8 in severe asthma: markers of systemic inflammation? , 2006, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  P. Paggiaro,et al.  Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients. , 2006, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[24]  I. Adcock,et al.  Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. , 2006, American journal of respiratory and critical care medicine.

[25]  K. Chung,et al.  Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy , 2006, Respiratory research.

[26]  Richard J Martin,et al.  Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. , 2006, American journal of respiratory and critical care medicine.

[27]  S. Schreiber,et al.  Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[28]  S. Georas,et al.  Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. , 2006, The Biochemical journal.

[29]  I. Adcock,et al.  Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. , 2004, The Journal of allergy and clinical immunology.

[30]  P. Barnes,et al.  Nuclear factor‐κB does not mediate the inhibitory effects of dexamethasone on granulocyte–macrophage colony‐stimulating factor expression , 2004, Immunology.

[31]  P. Barnes.  Corticosteroid resistance in airway disease. , 2004, Proceedings of the American Thoracic Society.

[32]  Isabelle Vachier,et al.  Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. , 2003, American journal of respiratory and critical care medicine.

[33]  I. Adcock,et al.  Corticosteroid-insensitive asthma: molecular mechanisms. , 2003, The Journal of endocrinology.

[34]  J. Dean,et al.  Post‐transcriptional regulation of gene expression by mitogen‐activated protein kinase p38 , 2003, FEBS letters.

[35]  R. Djukanović,et al.  The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[36]  M. Garabedian,et al.  Deciphering the Phosphorylation “Code” of the Glucocorticoid Receptor in Vivo * 210 , 2002, The Journal of Biological Chemistry.

[37]  K. J. Macleod,et al.  Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma. , 2002, The American journal of medicine.

[38]  I. Adcock,et al.  p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. , 2002, The Journal of allergy and clinical immunology.

[39]  S. Saccani,et al.  p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. , 2002, Nature immunology.

[40]  S. Saccani,et al.  p38-dependent marking of inflammatory genes for increased NF-κB recruitment , 2002, Nature Immunology.

[41]  J. Siekierka,et al.  p38α Mitogen-Activated Protein Kinase Is Activated by CD28-Mediated Signaling and Is Required for IL-4 Production by Human CD4+CD45RO+ T Cells and Th2 Effector Cells , 1999, The Journal of Immunology.

[42]  K. Roebuck.  Regulation of interleukin-8 gene expression. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[43]  D. Postma,et al.  Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society. , 1999, The European respiratory journal.

[44]  S. Logan,et al.  Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. Martin,et al.  Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma , 1995, The Journal of experimental medicine.

[46]  R. Dworski,et al.  New therapies for asthma. , 1994, Comprehensive therapy.

[47]  S. Szefler,et al.  Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. , 1993, Journal of immunology.