Polymorphisms in IL-4Rα Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13−/− Mice

Abstract

The development of airways hyperreactivity in allergic IL-13−/− mice is controversial and appears to correlate with the number of times that the original 129 × C57BL/6 founder strain has been crossed to the BALB/c background. In this investigation, we compared allergic responses in founder IL-13−/− mice crossed for either 5 (N5) or 10 (N10) generations to BALB/c mice. Whereas allergic N5 IL-13−/− mice developed airways hyperreactivity, tissue eosinophilia, elevated IgE, and pulmonary expression of Ym proteins, these processes were attenuated in N5 IL-13−/− mice treated with an IL-4-neutralizing Ab, and in N10 IL-13−/− mice. These data showed that IL-4 was more effective in regulating allergic responses in N5 IL-13−/− mice than in N10 IL-13−/− mice. To elucidate the mechanism associated with these observations, we show by restriction and sequence analysis that N5 IL-13−/− mice express the C57BL/6 form of IL-4Rα and N10 IL-13−/− mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4Rα from N5 IL-13−/− mice migrates with a slower electrophoretic mobility than IL-4Rα from N10 IL-13−/− mice, suggesting more extensive posttranslational modification of the N5 form. The Thre49Ile polymorphism in the extracellular domain of BALB/c IL-4Rα has been demonstrated to disrupt N-linked glycosylation of Asn47 and increase the dissociation rate of the IL-4Rα/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4Rα, which have been shown to affect the interaction with IL-4, correlate with the ability of IL-4 to regulate allergic responses in IL-13−/− mice.