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

Frank Blaeser, Paul J. Bryce, Nga Ho, Vidya Raman, Fatma Dedeoglu, Debra D. Donaldson, Raif S. Geha, Hans C. Oettgen, Talal A. Chatila*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Rα 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.

Original languageEnglish (US)
Pages (from-to)1189-1200
Number of pages12
JournalJournal of Experimental Medicine
Volume198
Issue number8
DOIs
StatePublished - Oct 20 2003

Keywords

  • Asthma
  • Immunoglobulin E
  • Insulin receptor substrate
  • Interleukin 4 receptor
  • Targeted mutagenesis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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