Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 46, Issue 5, Pages 703-713Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2011-0391OC
Keywords
resistin-like molecule-alpha; asthma; IL-4; IL-13R alpha 1
Funding
- National Institutes of Health [AI83450, AI045898, DK076893, HL097360]
- Buckeye Foundation
- Food Allergy Initiative
- Campaign Urging Research For Eosinophilic Disease
- United States-Israel Bi-National Science Foundation [2009222]
- Marie-Curie
- Veterans Administration
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Resistin-like molecule alpha (Relm-alpha) is one of the most up-regulated gene products in allergen- and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-alpha was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-a production, and the role of Relm-alpha after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-alpha was secreted into the airway lumen, dependent on both the IL-13 receptor-alpha 1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene-targeted mice demonstrate that Relm-alpha was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-alpha in the lungs. The differential regulation of Relm-alpha expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-alpha in acute experimental models of allergen-associated Th2 immune responses.
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