Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 206, Issue 10, Pages 2191-2204Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20091480
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Funding
- NIH [2R01AI065617, R01AI054471]
- National Heart, Lung, and Blood Institute Specialized Centers of Clinically Oriented Research
- National Institute of Allergy and Infectious Diseases Asthma and Allergic Diseases Cooperative Research Centers
- Human and Molecular Development Training [T32 HD007512]
- NIH/National Institute of Child Health and Human Development
- United States Department of Health and Human Service Ruth L. Kirschstein Institutional National Research Service [T32 CA009056]
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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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