title: Airway epithelial NF-κB activation promotes allergic sensitization to an innocuous inhaled antigen.
abstract: Activation of NF-κB in airway epithelium is observed in allergic asthma and is induced by inhalation of numerous infectious and reactive substances. Many of the substances that activate NF-κB in the airway epithelium are also capable of acting as adjuvants to elicit antigen-specific sensitization to concomitantly inhaled protein, thereby circumventing the inherent bias of the lung to promote tolerance to innocuous antigens. We have used a transgenic mouse inducibly expressing a constitutively active mutant of the inhibitor of nuclear factor κB (IκB) kinase β ((CA)IKKβ) that activates NF-κB only in nonciliated airway epithelial cells to test whether activation of this intracellular signaling pathway in this specific cell type is sufficient to establish a pulmonary environment permissive to the development of allergic sensitization to inhaled protein. When airway epithelial (CA)IKKβ was transiently expressed in antigen-naive mice only during initial inhalation of ovalbumin, the mice became allergically sensitized to the antigen. As a consequence, subsequent inhalation of ovalbumin alone led to an allergic asthma-like response that included airway hyperresponsiveness to methacholine, eosinophilia, mucus expression, elevated serum levels of antigen-specific IgE and IgG1, and splenic CD4(+) T cells that secreted T helper type 2 and type 17 cytokines in response to in vitro antigen restimulation. Furthermore, CD11c(+) cells in the mediastinal lymph nodes (MLN) of (CA)IKKβ-expressing mice displayed significantly elevated levels of activation markers. These data implicate airway epithelial NF-κB activation as a critical modulator of the adaptive immune response to inhaled antigens via the secretion of soluble mediators that affect the capacity of CD11c(+) cells to undergo maturation and promote antigen-specific allergic responses.
authors.affiliation: Department of Medicine, Vermont Lung Center, University of Vermont, Burlington, 05405, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Hodgkins
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D001249:Asthma / Q000276:immunology; D001980:Bronchi / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D039521:CD11c Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006967:Hypersensitivity / Q000276:immunology*; D001239:Inhalation; D008168:Lung / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D039521:CD11c Antigen; D016328:NF-kappa B