title: IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle.
abstract: In testing the hypothesis that interleukin-4 receptor alpha-subunit (IL-4R alpha)-coupled signaling mediates altered airway smooth muscle (ASM) responsiveness in the atopic sensitized state, isolated rabbit tracheal ASM segments were passively sensitized with immunoglobulin E (IgE) immune complexes, both in the absence and presence of an IL-4R alpha blocking antibody (anti-IL-4R alpha Ab). Relative to control ASM, IgE-sensitized tissues exhibited enhanced isometric constrictor responses to administered ACh and attenuated relaxation responses to isoproterenol. These proasthmatic-like effects were prevented in IgE-sensitized ASM that were pretreated with anti-IL-4R alpha Ab. In complementary experiments, IgE-sensitized cultured human ASM cells exhibited upregulated expression of IL-13 mRNA and protein, whereas IL-4 expression was undetected. Moreover, extended studies demonstrated that 1) exogenous IL-13 administration to naïve ASM elicited augmented contractility to ACh and impaired relaxation to isoproterenol, 2) these effects of IL-13 were prevented by pretreating the tissues with an IL-5 receptor blocking antibody, and 3) IL-13 administration induced upregulated mRNA expression and release of IL-5 protein from cultured ASM cells. Collectively, these findings provide new evidence demonstrating that the altered responsiveness of IgE-sensitized ASM is largely attributed to activation of an intrinsic Th2-type autocrine mechanism involving IL-13/IL-4R alpha-coupled release and action of IL-5 in the sensitized ASM itself.
authors.affiliation: Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. grunstein@email.chop.edu
authors.forename: M M
authors.initials: MM
authors.lastname: Grunstein
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.forename: J
authors.initials: J
authors.lastname: Leiter
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Whelan
authors.forename: J S
authors.initials: JS
authors.lastname: Grunstein
authors.forename: S
authors.initials: S
authors.lastname: Chuang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D018678:Cholinergic Agents / Q000494:pharmacology; D006801:Humans; D007114:Immunization; D007073:Immunoglobulin E / Q000276:immunology*; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009130:Muscle, Smooth / Q000276:immunology / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D019948:Receptors, Interleukin-4 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014132:Trachea / Q000276:immunology / Q000502:physiology*
chemical_list: D018678:Cholinergic Agents; D018793:Interleukin-13; D015848:Interleukin-5; D020033:Protein Isoforms; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007073:Immunoglobulin E; D000109:Acetylcholine