title: Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle β2 Adrenoceptors.
abstract: Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients.
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
authors.forename: Latifa
authors.initials: L
authors.lastname: Chachi
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Newby
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Amrani
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000420:Albuterol / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D048588:Benzoxazines / Q000494:pharmacology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D000068298:Fluticasone / Q000494:pharmacology; D000068759:Formoterol Fumarate / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D009130:Muscle, Smooth / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D017455:Receptors, IgE / Q000276:immunology; D019089:Stem Cell Factor / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D018343:Receptors, Adrenergic, beta-2; D017455:Receptors, IgE; D019089:Stem Cell Factor; D006632:Histamine; D000068298:Fluticasone; D000420:Albuterol; C549647:olodaterol; D000068759:Formoterol Fumarate