title: Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin.
abstract: Interleukin (IL)-13 is a central mediator of the processes underlying the induction of airways hyperreactivity (AHR) in the allergic lung. However, the mechanisms by which IL-13 induces AHR and the associated role of inflammatory infiltrates as effector cells has not been fully elucidated. In this investigation, we show that intratracheal administration of IL-13 induces AHR in the presence and absence of inflammation. The initial AHR response (peak, 6 to 24 h; preinflammatory phase [PIP]) was dissociated from inflammation (eosinophilia) and mucus hypersecretion but was critically regulated by signaling through the IL-4 receptor alpha chain (IL-4Ralpha) and signal transducers and activators of transcription (STAT)-6. The second response (> 24 h, inflammatory phase [IP]) was characterized by an amplified AHR, eosinophil accumulation, and mucus hypersecretion. These features of the IP were not observed in IL-4Ralpha- or STAT-6-deficient mice. To determine the role of eosinophils in the induction of IP AHR and mucus hypersecretion, we administered IL-13 to IL-5-, eotaxin-, and IL-5/eotaxin- deficient mice. IL-13-mediated eosinophil accumulation was significantly attenuated (but not ablated) in IL-5-, eotaxin-, or IL-5/eotaxin-deficient mice. However, IL-13-induced AHR and mucus secretion occurred independently of IL-5 and/or eotaxin. These findings demonstrate that IL-13 can induce AHR independently of these eosinophil regulatory cytokines and mucus hypersecretion. Furthermore, IL-13-induced AHR, eosinophilia, and mucus production are critically dependent on the IL-4Ralpha chain and STAT-6.
authors.affiliation: Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: S P
authors.initials: SP
authors.lastname: Hogan
authors.forename: P J
authors.initials: PJ
authors.lastname: Henry
authors.forename: K I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: A N
authors.initials: AN
authors.lastname: McKenzie
authors.forename: I G
authors.initials: IG
authors.lastname: Young
authors.forename: M E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: P S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000378:metabolism; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D007442:Intubation, Intratracheal; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009093:Mucus / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D016085:Bronchoconstrictor Agents; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018793:Interleukin-13; D015848:Interleukin-5; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016210:Methacholine Chloride; D015847:Interleukin-4