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Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma

Abstract

Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation1. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity2,3. Asthma is mediated by Th2 lymphocytes4,5,6,7, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma4,5,7,8,9,10,11, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia10,11. Furthermore, IL-13 delivery to the airway causes all of these effects10,11. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.

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Figure 1: Epi-hSTAT6 expression is limited to lung epithelial cells.
Figure 2: IL-13 acting only on epithelial cells results in airway hyperreactivity and mucus production.
Figure 3: Reconstitution of epithelial cell–specific STAT6 signaling is not sufficient for IL-13-induced inflammation, fibrosis or emphysema.

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Acknowledgements

We thank A. Atakilit, X.L. Bernstein, R. Ferrando, C. Hoyos, J. Mandac, M. Rodriguez, O. Shcherbakova, P. Woodruff and the staffs of the UCSF-Gladstone Institutes Transgenic Core Facility and the Mouse Physiology Core Facility of the UCSF Sandler Center for Basic Research in Asthma. This work was supported by the National Institutes of Health, the Sandler Family Foundation and the UCSF Howard Hughes Medical Institute Research Resources Program.

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Correspondence to David J. Erle.

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Kuperman, D., Huang, X., Koth, L. et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med 8, 885–889 (2002). https://doi.org/10.1038/nm734

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