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Syk tyrosine kinase participates in ₁-integrin signaling and inflammatory responses in airway epithelial cells

Departments of ¹Medicine, ²Laboratory Medicine and Pathology, and ³Physiology, University of Alberta, Edmonton, Alberta, Canada; ⁴Department of Immunology, Max Planck Institute of Infection Biology, Berlin, Germany; and ⁵University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 1 July 2004 ; accepted in final form 12 November 2004

The protein tyrosine kinase Syk is critically involved in immunoreceptor signaling in hematopoietic cells. Recent studies demonstrate Syk expression in nonhematopoietic cells, including fibroblasts, endothelial cells, hepatocytes, and breast epithelium. However, the role of Syk in these cells is uncertain. We hypothesized that Syk is expressed in respiratory epithelial cells (EC) and that it functions as a signaling molecule involved in inflammatory responses in the epithelium. With the use of immunohistochemistry, Western blot, PCR, and laser scanning confocal microscopy, Syk was detected in human, rat, and mouse bronchial epithelium in situ and in cultured human bronchial EC in primary cells and the cell lines HS-24 and BEAS-2B. Syk-dependent signaling pathways in EC were initiated by engagement of ₁-integrin receptors. Stimulation of ₁-integrin receptors by fibronectin or antibody cross-linking caused redistribution of Syk from a cytoplasmic to plasma membrane localization. In stimulated cells, Syk and ₁-integrin colocalized. In addition, following ₁-integrin receptor engagement, tyrosine phosphorylation of Syk was observed. Expression of the intercellular adhesion molecule-1 (ICAM-1) and production of IL-6, both important molecules in lung inflammation, was downregulated in EC treated with Syk small interfering RNA or Syk inhibitor piceatannol. We propose that Syk is involved in signaling pathways induced by integrin engagement in airway EC. Syk-mediated signaling regulates IL-6 and ICAM-1 expression and may be important in the pathophysiology of lung inflammation.

integrins; inflammation

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