Syk is downstream of intercellular adhesion molecule-1 and mediates human rhinovirus activation of p38 MAPK in airway epithelial cells.
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.
Wang
Xiaomin
X
Division of Respirology, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lau
Christine
C
Wiehler
Shahina
S
Pow
André
A
Mazzulli
Tony
T
Gutierrez
Carlos
C
Proud
David
D
Chow
Chung-Wai
CW
D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000201:enzymology / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000821:virology; D051379:Mice; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology* / Q000821:virology*; D012229:Rhinovirus / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000072377:Syk Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099149:Ezrin; C000606896:SYK protein, human; C000606897:Syk protein, mouse