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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 4, October, 2001 522-530

Interleukin-13 Mediates Airways Hyperreactivity through the IL-4 Receptor-Alpha Chain and STAT-6 Independently of IL-5 and Eotaxin

Ming Yang, Simon P. Hogan, Peter J. Henry, Klaus I. Matthaei, Andrew N. J. McKenzie, Ian G. Young, Marc E. Rothenberg, and Paul S. Foster

Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia; Department of Pharmacology, University of Western Australia, Perth, Australia; Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom; and Department of Pediatrics, Division of Pulmonary Medicine, Allergy and Clinical Immunology, Children's Hospital Medical Center, Cincinnati, Ohio

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.

Abbreviations: airways hyperreactivity, AHR; interleukin, IL; inflammatory phase, IP; monoclonal antibody, mAb; periodic acid-Schiff, PAS; phosphate-buffered saline, PBS; enhanced pause, Penh; preinflammatory phase, PIP; airway resistance, RL; standard error of the mean, SEM; signal transducer and activator of transcription-6, STAT-6; T helper, Th; wild-type, WT.




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