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Targeted Inactivation of the IL-4 Receptor Chain I4R Motif Promotes Allergic Airway Inflammation

¹ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
² Department of Pediatrics, Harvard Medical School, Boston, MA 02115
³ Department of Respiratory Disease, Wyeth Research, Cambridge, MA 02140
⁴ Department of Pathology and Immunology and the Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Talal A. Chatila, Dept. of Pediatrics, The David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095-1752. Phone: (310) 825-4125; Fax: (310) 206-4584; email: Tchatila{at}mednet.ucla.edu

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)R chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4–induced CD4⁺ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.

Key Words: interleukin 4 receptor • targeted mutagenesis • immunoglobulin E • insulin receptor substrate • asthma

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