title: Polymorphisms in IL-4R alpha 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 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-4Ralpha and N10 IL-13(-/-) mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4Ralpha from N5 IL-13(-/-) mice migrates with a slower electrophoretic mobility than IL-4Ralpha from N10 IL-13(-/-) mice, suggesting more extensive posttranslational modification of the N5 form. The Thre(49)Ile polymorphism in the extracellular domain of BALB/c IL-4Ralpha has been demonstrated to disrupt N-linked glycosylation of Asn(47) and increase the dissociation rate of the IL-4Ralpha/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4Ralpha, 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.
authors.affiliation: Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia 2601. dianne.webb@anu.edu.au
authors.forename: Dianne C
authors.initials: DC
authors.lastname: Webb
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Yeping
authors.initials: Y
authors.lastname: Cai
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D054392:Adipokines; D000595:Amino Acid Sequence; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000737:chemistry; D007073:Immunoglobulin E / Q000096:biosynthesis; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics; D037102:Lectins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000276:immunology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D021122:Protein Subunits / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology*; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; D006023:Glycoproteins; D018793:Interleukin-13; D037102:Lectins; D020033:Protein Isoforms; D021122:Protein Subunits; D019948:Receptors, Interleukin-4; D007073:Immunoglobulin E; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases