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Polymorphisms in IL-4R Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13^-/- Mice ¹

Dianne C. Webb^2,*, Klaus I. Matthaei^*, Yeping Cai^*, Andrew N. J. McKenzie and Paul S. Foster^*

^* Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia; and Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

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 x 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-4R and N10 IL-13^-/- mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4R from N5 IL-13^-/- mice migrates with a slower electrophoretic mobility than IL-4R 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-4R has been demonstrated to disrupt N-linked glycosylation of Asn⁴⁷ and increase the dissociation rate of the IL-4R/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4R, 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.

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