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Atopy and asthma: genetic variants of IL-4 and IL-13 signalling

https://doi.org/10.1016/S0167-5699(99)01492-9Get rights and content

Abstract

Recent genetic and functional studies highlight the importance of IL-4/IL-13 signalling in the development of asthma and atopy. Here, Taro Shirakawa and colleagues discuss genetic variants of IL-4/IL-13 signalling, and whether they promote asthma or atopy among different ethnic groups.

Section snippets

Ligands: IL-4 and IL-13

IL4 and IL13 are localized within 25 kb on the proximal portion of chromosome 5q31, to which genome searches have identified strong linkage with asthma and atopy5, 6. A dinucleotide repeat in the third intron of IL4 is linked to total serum IgE levels but not to asthma in Caucasian populations4, whereas linkage to both high IgE levels and asthma has been found in a Japanese population8. These findings support the candidacy of IL4 as an atopy locus on 5q31.

To date, five putative variants have

Receptors: IL-4R and IL-13R

The human IL-4R is a heterodimeric complex comprising the IL-4Rα chain and γc chain (Fig. 1)1. The IL-4Rα chain is also an essential component of IL-13R (Ref. 1). IL-4Rα-null mice lack IgE synthesis and Th2 immune reactions1, suggesting that the IL-4Rα chain is a crucial component for binding and signal transduction of both IL-4 and IL-13. A strong genetic linkage has been found between atopy and flanking markers to IL-4R on 16p12 (Ref. 7), whereas genome-wide searches by linkage have been

Signal transduction molecules

The IL-4Rα chain associates with JAK1 and the γc chain associates with JAK3, whereas IL-13Rα1 associates with Tyk2. These components are considered to be required for STAT6 activation1. However, JAK1 and STAT6, but not JAK3, are activated by IL-13, implying that STAT6 activation is due to STAT6 docking to the IL-4Rα chain1. STAT6-deficient mice lack IgE production and Th2 inflammatory reactions1, thus STAT6 is a crucial molecule for IL-4 and IL-13 signal transduction. Human STAT6 spanning 19 kb

Concluding remarks

The overall picture emerging from the genetic and functional analyses provides increasing evidence that there are major loci for atopy and asthma in relation to signalling of IL-4 and IL-13 through IL-4Rα–STAT6. IL-13 might be principal to asthma per se, while its receptors IL-4Rα and IL-13Rα1 drive atopy. IL-4Rα and STAT6 are essential for the action of both cytokines, and for the development of atopy and asthma. To date, however, no common variant of the genes in this pathway is associated

Acknowledgements

We thank Y. Yanagihara, R.T. Kreomer, H. Mitsuyasu, Y. Arinobu, N. Hamasaki, M. Kawai, T. Enomoto, Y. Dake, S. Sasaki, S. Kruse, A. Heinzmann, P-S. Gao and M.H. Roberts for their kind discussion.

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