Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis
- 20 May 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (20), 7240-7245
- https://doi.org/10.1073/pnas.0802465105
Abstract
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.Keywords
This publication has 31 references indexed in Scilit:
- Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor α1 chainNature Immunology, 2007
- Protective immune mechanisms in helminth infectionNature Reviews Immunology, 2007
- A Chitinase-like Protein in the Lung and Circulation of Patients with Severe AsthmaNew England Journal of Medicine, 2007
- Persistent Effects Induced by IL-13 in the LungAmerican Journal of Respiratory Cell and Molecular Biology, 2006
- IL-4 induces IL-13–independent allergic airway inflammationJournal of Allergy and Clinical Immunology, 2006
- Monocyte and macrophage heterogeneityNature Reviews Immunology, 2005
- Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesisJCI Insight, 2003
- Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2The Journal of Experimental Medicine, 2003
- Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune ResponseThe Journal of Experimental Medicine, 2003
- Interleukin-4 and lnterleukin-13: Their Similarities and DiscrepanciesInternational Reviews of Immunology, 1998