title: TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.
abstract: Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10-/-) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10-/-mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.
authors.forename: Leon A
authors.initials: LA
authors.lastname: Sokulsky
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia; Adam.Collison@newcastle.edu.au.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Collison
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.
authors.forename: Anna Le
authors.initials: AL
authors.lastname: Fevre
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.|Department of Gastroenterology and the Department of Respiratory and Sleep Medicine, John Hunter Children's Hospital, Newcastle, Newcastle, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Percival
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: Priority Research Centre for Lung Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; and.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Priority Research Centre for Lung Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; and.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: The Priority Research Centre GrowUpWell, Newcastle, Australia.|Department of Gastroenterology and the Department of Respiratory and Sleep Medicine, John Hunter Children's Hospital, Newcastle, Newcastle, Australia.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016022:Case-Control Studies; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D021181:Egg Hypersensitivity / Q000150:complications*; D057765:Eosinophilic Esophagitis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008868:Microtubule Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D000068299:Salmeterol Xinafoate / Q000008:administration & dosage / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D016207:Cytokines; D007377:Interleukin-3; D015848:Interleukin-5; D008868:Microtubule Proteins; D009687:Nuclear Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D010047:Ovalbumin; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases; D054648:Protein Phosphatase 2; D000094632:Thymic Stromal Lymphopoietin
keywords: MID 1; PP2A; TRAIL; eosinophilic esophagitis; salmeterol