title: Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice.
abstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse versus human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and the relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient but not necessary to induce AHR. Five genes known to promote smooth muscle migration, proliferation, and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics.
authors.affiliation: Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Perkins
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanase
authors.forename: George
authors.initials: G
authors.lastname: Smulian
authors.forename: Lucy
authors.initials: L
authors.lastname: Gildea
authors.forename: Tatyana
authors.initials: T
authors.lastname: Orekov
authors.forename: Crystal
authors.initials: C
authors.lastname: Potter
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D005260:Female; D005786:Gene Expression Regulation; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000502:physiology*
chemical_list: D000485:Allergens; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4