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J Allergy Clin Immunol. 2004 Sep;114(3):553-60.

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

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  • 1Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.

Abstract

BACKGROUND:

IL-13 is a key mediator of allergic asthma. IL-13 mediates its effects via its receptor, a heterodimer composed of IL-4R alpha and IL-13R alpha1. Polymorphic variants of both IL-13 and IL-4R alpha 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-4R alpha and of the atopy-associated variant V50R551 IL-4R alpha.

METHODS:

We used a mouse cell line stably expressing human IL-4R alpha and IL-13R alpha1 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-4R alpha (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-4R alpha.

CONCLUSION:

Either Q110 IL-13 variant or V50R551 IL-4R alpha 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.

PMID:
15356556
[PubMed - indexed for MEDLINE]
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