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The Journal of Experimental Medicine

Year: 2009  |  Volume: 206  |  Issue: 10  |  Page No.: 2191 - 2204

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

R Tachdjian, C Mathias, S Al Khatib, P. J Bryce, H. S Kim, F Blaeser, B. D O'Connor, D Rzymkiewicz, A Chen, M. J Holtzman, G. K Hershey, H Garn, H Harb, H Renz, H. C Oettgen and T. A. Chatila

Abstract

Polymorphisms in the interleukin-4 receptor chain (IL-4R) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4R has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4R–dependent signaling.

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