TY - JOUR
T1 - Polymorphisms in IL-4Rα Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13-/- Mice
AU - Webb, Dianne C.
AU - Matthaei, Klaus I.
AU - Cai, Yeping
AU - McKenzie, Andrew N.J.
AU - Foster, Paul S.
PY - 2004/1/15
Y1 - 2004/1/15
N2 - 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 Thre49 Ile polymorphism in the extracellular domain of BALB/c IL-4Rα has been demonstrated to disrupt N-linked glycosylation of Asn 47 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.
AB - 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 Thre49 Ile polymorphism in the extracellular domain of BALB/c IL-4Rα has been demonstrated to disrupt N-linked glycosylation of Asn 47 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.
UR - http://www.scopus.com/inward/record.url?scp=1642454710&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.172.2.1092
DO - 10.4049/jimmunol.172.2.1092
M3 - Article
SN - 0022-1767
VL - 172
SP - 1092
EP - 1098
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -