Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Pages (from-to) | 2191-204 |
Number of pages | 14 |
Journal | The Journal of experimental medicine |
Volume | 206 |
Issue number | 10 |
Publication status | Published - 28 Sept 2009 |
Peer-reviewed | Yes |
Externally published | Yes |
External IDs
PubMedCentral | PMC2757875 |
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Scopus | 70350447528 |
Keywords
Sustainable Development Goals
Keywords
- Alleles, Animals, Asthma/etiology, Humans, Immunoglobulin E/biosynthesis, Interleukin-13/physiology, Interleukin-4/biosynthesis, Mice, Mice, Transgenic, Mutation, Ovalbumin/immunology, Polymorphism, Genetic, Receptors, Cell Surface/genetics, STAT6 Transcription Factor/metabolism, Signal Transduction, Th2 Cells/immunology