title: Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A.
abstract: BACKGROUND
  β-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described in vitro.
  
  
  OBJECTIVE
  We sought to elucidate the molecular mechanisms by which β-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B-exacerbated allergic airways disease (AAD).
  
  
  METHODS
  Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]).
  
  
  RESULTS
  Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor κB subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A in vitro isolated from human airway epithelial cells.
  
  
  CONCLUSIONS
  Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits.
authors.affiliation: Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Hatchwell
authors.affiliation: Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Girkin
authors.affiliation: Medical Biochemistry Department, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Cancer Research Program and Hunter Cancer Research Alliance, Newcastle, Australia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Dun
authors.affiliation: Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Morten
authors.affiliation: Medical Biochemistry Department, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Cancer Research Program and Hunter Cancer Research Alliance, Newcastle, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Verrills
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, Australia.
authors.forename: Hamish D
authors.initials: HD
authors.lastname: Toop
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.affiliation: Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Paediatric Respiratory and Sleep Medicine Unit, Newcastle Children's Hospital, Kaleidoscope, Newcastle, Australia. Electronic address: Joerg.Mattes@newcastle.edu.au.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000009:adverse effects; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010850:Picornaviridae Infections / Q000276:immunology / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D012229:Rhinovirus / Q000276:immunology*; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D039741:Antigens, Dermatophagoides; D000068299:Salmeterol Xinafoate; D054648:Protein Phosphatase 2; D000420:Albuterol
keywords: (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol; Long-acting β(2)-agonist; allergy; asthma; chemokine; dexamethasone; exacerbation; formoterol; nuclear factor κB; protein phosphatase 2A; rhinovirus; salbutamol; salmeterol