Antigen-specific production of interleukin (IL)-13 and IL-5 cooperate to mediate IL-4Rα-independent airway hyperreactivity

Authors

  • Dianne C. Webb,

    Corresponding author
    1. Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    • Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia Fax: +61-26125-0415
    Search for more papers by this author
  • Surendran Mahalingam,

    1. Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    2. present address: Department of Biological Sciences, University of Wollongong, Wollongong, Australia
    Search for more papers by this author
  • Yeping Cai,

    1. Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Search for more papers by this author
  • Klaus I. Matthaei,

    1. Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Search for more papers by this author
  • Debra D. Donaldson,

    1. Wyeth Research (formerly Genetics Institute), Cambridge, USA
    Search for more papers by this author
  • Paul S. Foster

    1. Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Search for more papers by this author

Abstract

The pathogenesis of human asthma and the development of key features of pulmonary allergy in mouse models has been critically linked to IL-13. Analyses of the receptor components employed by IL-13 have shown that delivery of this cytokine to the airways of naive IL-4Rα gene targeted (IL-4Rα–/–) mice fails to induce disease, suggesting that this membrane protein is critical for transducing IL-13-mediated responses. The current study demonstrates that, in contrast to naive mice, T helper 2 bias, airways hyperreactivity (AHR) and tissue eosinophilia develop in Ovalbumin-sensitized IL-4Rα–/– mice and that these responses can be inhibited by the IL-13 antagonist sIL-13Rα2Fc. Therefore, antigen stimulation induces an IL-13-regulated response that is independent of IL-4Rα. To determine the role of IL-5 and eosinophils in the development of disease in antigen-exposed IL-4Rα–/– mice, pulmonary allergy was examined in mice deficient in both factors. IL-4Rα/IL-5–/– mice were significantly defective in their ability to produce IL-13 and failed to develop AHR, suggesting that IL-5 indirectly regulates AHR in allergic IL-4Rα–/– mice by an IL-13-dependent mechanism. Collectively, these results demonstrate that IL-13-dependent processes regulating the development of AHR and T helper bias persist in the inthe lungs of allergic IL-4Rα–/– mice.

Ancillary