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Airway Epithelial STAT3 Is Required for Allergic Inflammation in a Murine Model of Asthma¹

Marina C. Simeone-Penney^*, Mariano Severgnini^*,¶, Powen Tu^*,¶, Robert J. Homer, Thomas J. Mariani, Lauren Cohn and Amy R. Simon^2,*,¶

^* Department of Physiology, Tufts University School of Medicine, Boston, MA 02111; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; Pulmonary Division, Brigham and Women’s Hospital, Boston, MA 02115; Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, CT 06520; and ^¶ Pulmonary and Critical Care Division, Tufts-New England Medical Center, Boston, MA 02111

The STAT3 transcription factor is critical for cytokine signaling and the acute phase response, but its role in allergic asthma is largely undefined. To investigate the role of STAT3 in mediating allergic inflammation, we used chemical and genetic approaches to inactivate STAT3 in the airway epithelium of mice. In a murine model of chronic asthma, we demonstrate that the administration of house dust mite (HDM) leads to robust STAT3 activation in the airway epithelium, smooth muscle, and immune cells in the lungs of C57BL/6 mice. To investigate the role of STAT3 in HDM-induced airway inflammation, a conditional knockout of STAT3 in the airway epithelium was generated, e-STAT3^–/–. We determined that e-STAT3^–/– mice had a significant decrease in HDM-induced airway eosinophilia, lung Th2 accumulation, and chemokines compared with wild-type animals. Importantly, the e-STAT3^–/– mice had a significant decrease in airway hyperresponsiveness to methacholine. The administration of two STAT kinase inhibitors diminished STAT3 activation and markedly abrogated the HDM-induced lung inflammation. These findings suggest that STAT3 acts as a novel epithelial regulator of the allergic response by altering Th2 cell recruitment and effector function, and thus, targeting this molecule may provide the basis for a novel asthma therapy.

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 a National Heart Lung and Blood Institute Grant RO1HL-68753-01A1.

² Address correspondence and reprint requests to Dr. Amy R. Simon, Pulmonary and Critical Care Division (Box 369), 750 Washington Street, Boston, MA 02111. E-mail address: amy.simon{at}tufts.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BALF, bronchoalveolar lavage fluid; e-STAT3, epithelial STAT3; HDM, house dust mite; i.n., intranasal(ly); KO, knockout; MCh, methacholine; p-STAT3, phospho-STAT3; TARC, thymus and activation-regulated chemokine; TyrA1, tyrphostin A1; WT, wild type.

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