Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma.
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.
Tachdjian
Raffi
R
Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Mathias
Clinton
C
Al Khatib
Shadi
S
Bryce
Paul J
PJ
Kim
Hong S
HS
Blaeser
Frank
F
O'Connor
Brian D
BD
Rzymkiewicz
Danuta
D
Chen
Andrew
A
Holtzman
Michael J
MJ
Hershey
Gurjit K
GK
Garn
Holger
H
Harb
Hani
H
Renz
Harald
H
Oettgen
Hans C
HC
Chatila
Talal A
TA
D000483:Alleles; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010047:Ovalbumin / Q000276:immunology; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
D007073:Immunoglobulin E; D018793:Interleukin-13; D015847:Interleukin-4; D010047:Ovalbumin; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit