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

Raffi Tachdjian, Clinton Mathias, Shadi Al Khatib, Paul J. Bryce, Hong S. Kim, Frank Blaeser, Brian D. O'Connor, Danuta Rzymkiewicz, Andrew Chen, Michael J. Holtzman, Gurjit K. Hershey, Holger Garn, Hani Harb, Harald Renz, Hans C. Oettgen, Talal A. Chatila

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56 Scopus citations

Abstract

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) 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-4Rα 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-4Rα-dependent signaling.

Original languageEnglish (US)
Pages (from-to)2191-2204
Number of pages14
JournalJournal of Experimental Medicine
Volume206
Issue number10
DOIs
StatePublished - Sep 28 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tachdjian, R., Mathias, C., Khatib, S. A., Bryce, P. J., Kim, H. S., Blaeser, F., O'Connor, B. D., Rzymkiewicz, D., Chen, A., Holtzman, M. J., Hershey, G. K., Garn, H., Harb, H., Renz, H., Oettgen, H. C., & Chatila, T. A. (2009). Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. Journal of Experimental Medicine, 206(10), 2191-2204. https://doi.org/10.1084/jem.20091480