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

Raffi Tachdjian(University of California, Los Angeles), Clinton B. Mathias(Harvard University), Shadi Al Khatib(University of California, Los Angeles), Paul Bryce(Harvard University), Hong S. Kim(University of California, Los Angeles), Frank Blaeser(Leipzig University), Brian D. O’Connor(University of California, Los Angeles), Danuta M. Rzymkiewicz(University of California, Los Angeles), Andrew Chen(University of California, Los Angeles), Michael J. Holtzman(Washington University in St. Louis), Gurjit K. Khurana Hershey(Cincinnati Children's Hospital Medical Center), Holger Garn(Philipps University of Marburg), Hani Harb(Philipps University of Marburg), Harald Renz(Philipps University of Marburg), Hans C. Oettgen(Harvard University), Talal A. Chatila(University of California, Los Angeles)
The Journal of Experimental Medicine
September 21, 2009
10.1084/jem.20091480
Cited by 77Open Access
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Abstract

Polymorphisms in the interleukin-4 receptor alpha chain (IL-4R alpha) 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 alpha 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 alpha-dependent signaling.

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