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The Journal of Immunology, 2009, 182, 1631 -1640
Copyright © 2009 by The American Association of Immunologists, Inc.
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The Critical Role of Epithelial-Derived Act1 in IL-17- and IL-25-Mediated Pulmonary Inflammation1

Shadi Swaidani*,{ddagger}, Katarzyna Bulek*, Zizhen Kang*, Caini Liu*, Yi Lu*, Weiguo Yin*, Mark Aronica{dagger} and Xiaoxia Li2,*

* Department of Immunology and {dagger} Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, OH 44195; and {ddagger} Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Research Grant R01AI065470.

2 Address correspondence and reprint requests to Dr. Xiaoxia Li, Department of Immunology, Cleveland Clinic, Cleveland, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: lix{at}ccf.org

3 Abbreviations used in this paper: TRAF, TNFR-associated factor; BAL, bronchoalveolar lavage.

4 The online version of this article contains supplementary material.


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The JI 2009 182: 1227-1228. [Full Text]  





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