title: TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis.
abstract: BACKGROUND
  Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus defined by eosinophil infiltration and tissue remodeling with resulting symptoms of esophageal dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) promotes inflammation through upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2Ac, resulting in increased nuclear factor κB activation.
  
  
  OBJECTIVE
  We sought to elucidate the role of TRAIL in EoE.
  
  
  METHODS
  We used Aspergillus fumigatus to induce EoE in TRAIL-sufficient (wild-type) and TRAIL-deficient (TRAIL(-/-)) mice and targeted MID1 in the esophagus with small interfering RNA. We also treated mice with recombinant thymic stromal lymphopoietin (TSLP) and TRAIL.
  
  
  RESULTS
  TRAIL deficiency and MID1 silencing with small interfering RNA reduced esophageal eosinophil and mast cell numbers and protected against esophageal circumference enlargement, muscularis externa thickening, and collagen deposition. MID1 expression and nuclear factor κB activation were reduced in TRAIL(-/-) mice, whereas protein phosphatase 2Ac levels were increased compared with those seen in wild-type control mice. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGFB, and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL(-/-) mice and recombinant TRAIL induced esophageal TSLP expression in vivo in the absence of allergen. Post hoc analysis of gene array data demonstrated significant upregulation of TRAIL and MID1 in a cohort of children with EoE compared with that seen in controls.
  
  
  CONCLUSIONS
  TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy, and expression of inflammatory effector chemokines and cytokines in experimental EoE.
authors.affiliation: Experimental and Translational Respiratory Medicine, 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. Electronic address: Adam.Collison@newcastle.edu.au.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Collison
authors.affiliation: Experimental and Translational Respiratory Medicine, 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: Leon A
authors.initials: LA
authors.lastname: Sokulsky
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Division of Allergy and Immunology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Sherrill
authors.affiliation: Department of Gastroenterology, Newcastle Children's Hospital, Newcastle, Australia; Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: Experimental and Translational Respiratory Medicine, 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: Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Talley
authors.affiliation: Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.
authors.forename: Marjorie M
authors.initials: MM
authors.lastname: Walker
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Division of Allergy and Immunology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Experimental and Translational Respiratory Medicine, 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; Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia; Paediatric Respiratory and Sleep Medicine Department, Newcastle Children's Hospital, Kaleidoscope, Newcastle, Australia.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D057765:Eosinophilic Esophagitis / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D004947:Esophagus / Q000382:microbiology / Q000473:pathology / Q000502:physiology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D023421:Models, Animal; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D011506:Proteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D003094:Collagen; C109037:Mid1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000094632:Thymic Stromal Lymphopoietin
keywords: CCL11; CCL20; CCL24; Eosinophilic esophagitis; IL-25; TNF-related apoptosis-inducing ligand; allergy; cytokine; fibrosis; midline-1; nuclear factor κB; protein phosphatase 2Ac; thymic stromal lymphopoietin; tissue remodeling