title: Steroid-insensitive ERK1/2 activity drives CXCL8 synthesis and neutrophilia by airway smooth muscle.
abstract: Severe or refractory asthma affects 5 to 15% of all patients with asthma, but is responsible for more than half of the health burden associated with the disease. Severe asthma is characterized by a dramatic increase in smooth muscle and airway inflammation. Although glucocorticoids are the mainstay of treatment in asthma, they are unable to fully control the disease in individuals with severe asthma. We found that airway smooth muscle cells (ASMCs) from individuals with severe asthma showed elevated activities of the ERK1/ERK2 and p38 MAPK pathways despite treatment with oral and inhaled glucocorticoids, which increased the expression of DUSP1, a phosphatase shown to limit p38 MAPK activity. In ex vivo ASMCs, TNF-α but not IL-17A induced expression of the neutrophil chemoattractant CXCL8. Moreover, TNF-α led to up-regulation of the ERK1/ERK2 and p38 MAPKs pathways, with only the latter being sensitive to pretreatment with the glucocorticoid dexamethasone. In contrast to epithelial and endothelial cells, TNF-α-stimulated CXCL8 synthesis was dependent on ERK1/ERK2 but not on p38 MAPK. Moreover, suppressing ERK1/ERK2 activation prevented neutrophil recruitment by ASMCs, whereas suppressing p38 MAPK activity had no impact. Taken together, these results highlight the ERK1/ERK2 MAPK cascade as a novel and attractive target in severe asthma because the activation of this pathway is insensitive to the action of glucocorticoids and is involved in neutrophil recruitment, contributing the to inflammation seen in the disease.
authors.affiliation: Meakins-Christie Laboratories, McGill University Heath Centre Research Institute, Montréal, Canada. simon.rousseau@mcgill.ca
authors.forename: Stephanie
authors.initials: S
authors.lastname: Robins
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.forename: Amanda
authors.initials: A
authors.lastname: Schachter
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Mogas
authors.forename: Ron
authors.initials: R
authors.lastname: Olivenstein
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D005938:Glucocorticoids; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1