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1: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7240-5. Epub 2008 May 14.
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Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis.

Munitz A, Brandt EB, Mingler M, Finkelman FD, Rothenberg ME.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.

IL-13 and IL-4 are central T helper 2 (Th2) cytokines in the immune system and potent activators of inflammatory responses and fibrosis during Th2 inflammation. Recent studies using Il13ra1(-/-) mice have demonstrated a critical role for IL-13 receptor (IL-13R) alpha1 in allergen-induced airway responses. However, these observations require further attention especially because IL-4 can induce similar lung pathology to IL-13, independent of IL-13, and is still present in the allergic lung. Thus, we hypothesized that IL-13Ralpha1 regulates IL-4-induced responses in the lung. To dissect the role of IL-13Ralpha1 and the type I and II IL-4Rs in experimental asthma, we examined lung pathology induced by allergen, IL-4, and IL-13 challenge in Il13ra1(-/-) mice. We report that IL-13Ralpha1 is essential for baseline IgE production, but Th2 and IgE responses to T cell-dependent antigens are IL-13Ralpha1-independent. Furthermore, we demonstrate that increased airway resistance, mucus, TGF-beta, and eotaxin(s) production, but not cellular infiltration, are critically dependent on IL-13Ralpha1. Surprisingly, our results identify a CCR3- and IL-13Ralpha1-independent pathway for lung eosinophilia. Global expression profiling of lungs from mice stimulated with allergen or IL-4 demonstrated that marker genes of alternatively activated macrophages are differentially regulated by the type I and type II IL-4R. Taken together, our data provide a comprehensive mechanistic analysis of the critical role by which IL-13Ralpha1 mediates allergic lung pathology and highlight unforeseen roles for the type II IL-4R.

Publication Types:
PMID: 18480254 [PubMed - indexed for MEDLINE]

PMCID: PMC2386078