title: Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma.
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.
authors.affiliation: Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Raffi
authors.initials: R
authors.lastname: Tachdjian
authors.forename: Clinton
authors.initials: C
authors.lastname: Mathias
authors.forename: Shadi
authors.initials: S
authors.lastname: Al Khatib
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bryce
authors.forename: Hong S
authors.initials: HS
authors.lastname: Kim
authors.forename: Frank
authors.initials: F
authors.lastname: Blaeser
authors.forename: Brian D
authors.initials: BD
authors.lastname: O'Connor
authors.forename: Danuta
authors.initials: D
authors.lastname: Rzymkiewicz
authors.forename: Andrew
authors.initials: A
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Hershey
authors.forename: Holger
authors.initials: H
authors.lastname: Garn
authors.forename: Hani
authors.initials: H
authors.lastname: Harb
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
authors.forename: Hans C
authors.initials: HC
authors.lastname: Oettgen
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: 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
chemical_list: 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