(The Rockefeller University Press, 2009) Tachdjian, Raffi; Al Khatib, Shadi; Bryce, Paul J.; Kim, Hong S.; Blaeser, Frank; O'Connor, Brian D.; Rzymkiewicz, Danuta; Holtzman, Michael J.; Hershey, Gurjit K.; Garn, Holger; Harb, Hani; Chatila, Talal A.; Mathias, Clinton B.; Chen, Andrew; Renz, Harald; Oettgen, Hans
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.
