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* Division of Respirology,
Division of Infectious Diseases, and
Multi-Organ Transplantation Unit, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and
Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
The airway epithelium is the primary target of inhaled pathogens such as human rhinovirus (HRV). Airway epithelial cells express ICAM-1, the major receptor for HRV. HRV binding to ICAM-1 mediates not only viral entry and replication but also a signaling cascade that leads to enhanced inflammatory mediator production. The specific signaling molecules and pathways activated by HRV-ICAM-1 interactions are not well characterized, although studies in human airway epithelia implicate a role for the p38 MAPK in HRV-induced cytokine production. In the current study, we report that Syk, an important immunoregulatory protein tyrosine kinase, is highly expressed by primary and cultured human airway epithelial cells and is activated in response to infection with HRV16. Biochemical studies revealed that ICAM-1 engagement by HRV and cross-linking Abs enhanced the coassociation of Syk with ICAM-1 and ezrin, a cytoskeletal linker protein. In polarized airway epithelial cells, Syk is diffusely distributed in the cytosol under basal conditions but, following engagement of ICAM-1 by cross-linking Abs, is recruited to the plasma membrane. The enhanced Syk-ICAM-1 association following HRV exposure is accompanied by Syk phosphorylation. ICAM-1 engagement by HRV and cross-linking Abs also induced phosphorylation of p38 in a Syk-dependent manner, and conversely, knockdown of Syk by short interfering (si)RNA substantially diminished p38 activation and IL-8 gene expression. Taken together, these observations identify Syk as an important mediator of the airway epithelial cell inflammatory response by modulating p38 phosphorylation and IL-8 gene expression following ICAM-1 engagement by HRV.
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 is supported by grants from the Ontario Thoracic Society, the Canadian Institutes of Health Research, the J. P. Bickell Foundation, and the Canadian Foundation for Innovation and Ontario Innovation Trust.
2 Address correspondence and reprint requests to Dr. Chung-Wai Chow, University of Toronto, 1 King’s College Circle, Room 6270, Toronto, Ontario M5S 1A8, Canada. E-mail address: cw.chow{at}utoronto.ca
3 Abbreviations used in this paper: HRV, human rhinovirus; siRNA, short interfering RNA; hSAEC, human small airway epithelial cell; MKK, MAP kinase kinase.
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