title: Airway epithelial NF-κB activation promotes the ability to overcome inhalational antigen tolerance.
abstract: BACKGROUND
  Inhalational antigen tolerance typically protects against the development of allergic airway disease but may be overcome to induce allergic sensitization preceding the development of asthma.
  
  
  OBJECTIVE
  We examined in vivo whether pre-existing inhalational antigen tolerance could be overcome by activation of the transcription factor NF-κB in conducting airway epithelial cells, and used a combination of in vivo and in vitro approaches to examine the mechanisms involved.
  
  
  METHODS
  Wild-type and transgenic mice capable of expressing constitutively active IκB kinase β (CAIKKβ) in airway epithelium were tolerized to inhaled ovalbumin. Twenty-eight days later, the transgene was transiently expressed and mice were exposed to inhaled OVA on Day 30 in an attempt to overcome inhalational tolerance.
  
  
  RESULTS
  Following ovalbumin challenge on days 40-42, CAIKKβ mice in which the transgene had been activated exhibited characteristic features of allergic airway disease, including airway eosinophilia and methacholine hyper-responsiveness. Increases in the CD103(+) and CD11b(HI) lung dendritic cell populations were present in CAIKKβ mice on Day 31. Bronchoalveolar lavage from mice expressing CAIKKβ mice induced CD4(+) T cells to secrete T(H)2 and T(H)17 cytokines, an effect that required IL-4 and IL-1 signalling, respectively. CAIKKβ mice on Dox demonstrated increased numbers of innate lymphoid type 2 cells (ILC2) in the lung, which also exhibited elevated mRNA expression of the T(H)2-polarizing cytokine IL-4. Finally, airway epithelial NF-kB activation induced allergic sensitization in CAIKKβ mice on Dox that required IL-4 and IL-1 signalling in vivo.
  
  
  CONCLUSIONS
  Our studies demonstrate that soluble mediators generated in response to airway epithelial NF-κB activation orchestrate the breaking of inhalational tolerance and allergic antigen sensitization through the effects of soluble mediators, including IL-1 and IL-4, on pulmonary dendritic cells as well as innate lymphoid and CD4(+) T cells.
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Ather
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Foley
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Suratt
authors.affiliation: Department of Surgery, University of Vermont, Burlington, VT, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Boyson
authors.affiliation: Vermont Lung Center, Division of Pulmonary Disease and Critical Care, Department of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Poynter
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D007108:Immune Tolerance; D007113:Immunity, Innate; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D016210:Methacholine Chloride / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000941:Antigens; D018836:Inflammation Mediators; D007375:Interleukin-1; D016328:NF-kappa B; D016210:Methacholine Chloride; D015847:Interleukin-4
keywords: NF-κB; T regulatory cells; allergic airway disease; dendritic cells; inhalational antigen tolerance