Targeted inactivation of the IL-4 receptor α chain 14R motif promotes allergic airway inflammation

The insulin/interleukin-4 (IL-4) receptor (14R,) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Ralpha 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 motifs 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, tip-regulation of IL-4-responsive gene products, and Th cell differentiation tinder Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveriess, tissue eosinophilia, and mucus production. These results define an important role for the 14R motif in regulating allergic inflammation.