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.
Targeted Inactivation of the IL-4 Receptor α Chain I4R Motif Promotes Allergic Airway Inflammation
Abbreviations used in this paper: AHR, airway hyperresponsiveness; AID, activation-induced cytidine deaminase; BAL, bronchoalveolar lavage; CSR, class switch recombination; DC-PCR, digestion-circularization PCR; ES, embryonic stem; GLT, germline transcripts; I4R, insulin/IL-4 receptor; IL-4, interleukin-4; IRS, insulin receptor substrate; ITIM, immunoreceptor tyrosine-based inhibitory motif; PI3-K, phosphatidylinositol 3′-kinase; PTB, phosphotyrosine-binding domain; SH, Src homology domain; SHP, SH2-containing tyrosine phosphatase.
Frank Blaeser, Paul J. Bryce, Nga Ho, Vidya Raman, Fatma Dedeoglu, Debra D. Donaldson, Raif S. Geha, Hans C. Oettgen, Talal A. Chatila; Targeted Inactivation of the IL-4 Receptor α Chain I4R Motif Promotes Allergic Airway Inflammation . J Exp Med 20 October 2003; 198 (8): 1189–1200. doi: https://doi.org/10.1084/jem.20030471
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