Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants

• Published in: Journal of allergy and clinical immunology Vol. 114; no. 3; pp. 553 - 560
• Main Authors: Chen, Weiguo, Ericksen, Mark B., Levin, Linda S., Khurana Hershey, Gurjit K.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.09.2004; Elsevier; Elsevier Limited
• Subjects: Animals; Asthma - genetics; Asthma - immunology; atopy; B-Lymphocytes; Biological and medical sciences; Cell Line; cytokine receptors; cytokines; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes; Genetic Variation; Genetics; Humans; Hypersensitivity, Immediate - genetics; Hypersensitivity, Immediate - immunology; Immunopathology; Interleukin-13 - genetics; Kinases; Laboratory animals; Medical sciences; Mice; Mice, Inbred BALB C; Polymorphism, Single Nucleotide; Receptors, Interleukin-4 - genetics; Signal Transduction; Studies; Transfection; STAT; SNP; signal transduction; atopy; Genetics; cytokines; Penh; AHR; cytokine receptors; Allergy; Immunopathology; Signal transduction; Immunology; Genetic variant; Cytokine; Atopy; Biological receptor
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2004.04.044

IL-13 is a key mediator of allergic asthma. IL-13 mediates its effects via its receptor, a heterodimer composed of IL-4Rα and IL-13Rα1. Polymorphic variants of both IL-13 and IL-4Rα have been shown to be associated with atopy. We examined the functional consequences of the Q110 IL-13 variant in vitro and in vivo to determine whether it displays enhanced functional activity compared with R110 IL-13, both in the context of I50Q551 IL-4Rα and of the atopy-associated variant V50R551 IL-4Rα. We used a mouse cell line stably expressing human IL-4Rα and IL-13Rα1 that readily responds to human IL-4 and IL-13. For in vivo analyses, we used BALB/c mice. The Q110 IL-13 variant displayed significantly increased activity compared with R110 IL-13. Furthermore, mice treated with Q110 IL-13 variant displayed increased airways hyperresponsiveness relative to R110 IL-13. We then examined the functional consequences of Q110 IL-13 variant in combination with an atopy-associated variant of its receptor, IL-4Rα (V50R551). Q110 IL-13 variant had increased activity on these cells as well, and, strikingly, the effect was greater than that observed in cells expressing I50Q551 IL-4Rα. Either Q110 IL-13 variant or V50R551 IL-4Rα variant has enhanced function alone, but the 2 together have a synergistic effect on IL-13–dependent gene induction. Our data demonstrate the importance of relatively small individual differences in gene products from common single nucleotide polymorphisms that may result in larger combined differences. Furthermore, a relatively modest change in function from a single nucleotide polymorphism can result in an important biological difference in vivo.