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Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells¹

Ali Saleh^*, Lianyu Shan^*, Andrew J. Halayko, Sam Kung^* and Abdelilah S. Gounni^2,*

^* Department of Immunology and Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

IL-17A has been shown to be expressed at higher levels in respiratory secretions from asthmatics and to correlate with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanism remains unknown. We previously demonstrated that IL-17A mediates CC chemokine (CCL11) production from human airway smooth muscle (ASM) cells. In this study, we demonstrate that STAT3 activation is critical in IL-17A-mediated CCL11 expression in ASM cells. IL-17A mediated a rapid phosphorylation of STAT3 but not STAT6 or STAT5 in ASM cells. Interestingly, transient transfection with wild-type or mutated CCL11 promoter constructs showed that IL-17A-mediated CCL11 expression relies on the STAT6 binding site. However, STAT3 but not STAT6 in vivo binding to the CCL11 promoter was detected following IL-17A stimulation of ASM cells. Overexpression of DN STAT3 (STAT3β) abolishes IL-17A-induced CCL11 promoter activity. This effect was not observed with STAT6 DN or the STAT3 mutant at Ser⁷²⁷. Interestingly, disruption of STAT3 activity with the SH2 domain binding peptide, but not with control peptide, results in a significant reduction of IL-17A-mediated STAT3 phosphorylation and CCL11 promoter activity. IL-17A-mediated CCL11 promoter activity and mRNA were significantly diminished in STAT3- but not STAT6-silenced ASM cells. Finally, IL-17A-induced STAT3 phosphorylation was sensitive to pharmacological inhibitors of JAK2 and ERK1/2. Taken together, our data provide the first evidence of IL-17A-mediated gene expression via STAT3 in ASM cells. Collectively, our results raise the possibility that the IL-17A/STAT3 signaling pathway may play a crucial role in airway inflammatory responses.

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 Canadian Institutes of Health Research Grant MOP 53104 to (A.S.G.).

² Address correspondence and reprint requests to Dr. Abdelilah S. Gounni, Department of Immunology, Faculty of Medicine, University of Manitoba, 606 Basic Medical Sciences Building, 730 William Avenue, Winnipeg, R3E0W3 Manitoba, Canada. E-mail address: gounni{at}cc.umanitoba.ca

³ Abbreviations used in this paper: ASM, airway smooth muscle; ChIP, chromatin immunoprecipitation; DN, dominant negative; RLU, relative luciferase unit; ShRNA, short hairpin RNA; tGFP, turboGFP; WT, wild type.