Abstract
IL-25 initiates, promotes, and augments Th2 immune responses. In this study, we report that Act1, a key component in IL-17-mediated signaling, is an essential signaling molecule for IL-25 signaling. Although Act1-deficient mice showed reduced expression of KC (CXCL1) and neutrophil recruitment to the airway compared with wild-type mice in response to IL-17 stimulation, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia. Using a mouse model of allergic pulmonary inflammation, we observed diminished Th2 responses and lung inflammation in Act1-deficient mice compared with wild-type mice. Importantly, Act1 deficiency in epithelial cells reduced the phenotype of allergic pulmonary inflammation due to loss of IL-17-induced neutrophilia and IL-25-induced eosinophilia, respectively. These results demonstrate the essential role of epithelial-derived Act1 in allergic pulmonary inflammation through the distinct impact of the IL-17R-Act1 and IL-25R-Act1 axes. Such findings are crucial for the understanding of pathobiology of atopic diseases, including allergic asthma, which identifies Act1 as a potential therapeutic target.