title: Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation.
abstract: IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6(-/-) mice. STAT6(-/-) mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Manni
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; and.
authors.forename: Sivanarayana
authors.initials: S
authors.lastname: Mandalapu
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; and.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McHugh
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477.
authors.forename: M Merle
authors.initials: MM
authors.lastname: Elloso
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Dudas
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224; and john.alcorn@chp.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004351:Drug Resistance; D015151:Immunoblotting; D018793:Interleukin-13 / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D008679:Metaplasia / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009093:Mucus / Q000276:immunology; D016133:Polymerase Chain Reaction; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D059467:Transcriptome
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17