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

Abstract

Background 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. Objective 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. Methods 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. Results 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. Conclusion 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.