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¹ Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and ² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
³ Department of Pediatrics, Harvard Medical School, Boston, MA 02115
⁴ Institute of Transfusion Medicine, University of Leipzig, 04103 Leipzig, Germany
⁵ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
⁶ Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
⁷ Department of Clinical Chemistry and Molecular Diagnostics, Hospital of the Philipps-University, 35033 Marburg, Germany

CORRESPONDENCE Talal A. Chatila: Tchatila{at}mednet.ucla.edu

Polymorphisms in the interleukin-4 receptor chain (IL-4R) 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 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–dependent signaling.

Abbreviations used: AHR, airway hyperresponsiveness; ANOVA, analysis of variance; BAL, bronchoalveolar lavage; BMDM, bone marrow–derived macrophage; ES, embryonic stem; Het, heterozygote; ITIM, immunoreceptor tyrosine-based inhibitory motif; MAPK, mitogen-activated protein kinase; MBP1, major basic protein 1; PAS, periodic acid–Schiff; PI3, phosphatidylinositol 3; TEC, tracheal airway epithelial cell.

© 2009 Tachdjian et al.
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