title: Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium.
abstract: BACKGROUND
  Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation.
  
  
  OBJECTIVE
  The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium.
  
  
  METHODS
  Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules.
  
  
  RESULTS
  Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs.
  
  
  CONCLUSIONS
  The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.|Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Uchida
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Anderson
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Squillace
authors.affiliation: Departments of Integrated Biology and Physiology and Animal Science, University of Minnesota, St. Paul, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Patil
authors.affiliation: Departments of Integrated Biology and Physiology and Animal Science, University of Minnesota, St. Paul, MN, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Maniak
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: H
authors.identifier: http://orcid.org/0000-0002-6854-2936
authors.initials: H
authors.lastname: Kita
authors.affiliation: Departments of Integrated Biology and Physiology and Animal Science, University of Minnesota, St. Paul, MN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: O'Grady
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000485:Allergens / Q000276:immunology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D000067596:Interleukin-33 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000975:Antioxidants; D000067596:Interleukin-33; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; D000255:Adenosine Triphosphate; C445068:bardoxolone methyl; D002118:Calcium
keywords: IL-33; airway epithelial cells; asthma; lung; nuclear factor-erythroid-2-related factor 2; reactive oxygen species