International Immunology Advance Access originally published online on January 8, 2008
International Immunology 2008 20(3):353-363; doi:10.1093/intimm/dxm146
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FAK-mediated activation of ERK for eosinophil migration: a novel mechanism for infection-induced allergic inflammation
1 Department of Chemical Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong
2 Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology Foundation, Macau, China
Correspondence to: C. W. -K. Lam; E-mail: waikeilam{at}cuhk.edu.hk
Bacterial and viral infections often induce the exacerbation of allergic diseases. In this study, we investigated the activation of human eosinophils by different microbial products via Toll-like receptors (TLRs). The underlying intracellular mechanism involving activation of extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK), an integrin-associated focal adhesion molecule, was also examined. Seven TLR ligands were studied for their abilities in promoting survival, modulating the expression of adhesion molecules and facilitating chemotactic migration of eosinophils. While peptidoglycan (PGN) (TLR2 ligand) showed the most prominent effects, flagellin (TLR5 ligand) and imiquimod R837 (TLR7 ligand) were also effective in activating eosinophils. However, little or no effect was observed for double-stranded polyinosinic–polycytidylic acid (TLR3 ligand), ultra-purified LPS (TLR4 ligand), single-stranded RNA (ssRNA) (TLR8 ligand) and CpG-DNA (TLR9 ligand). Further investigation confirmed that PGN, flagellin and R837 commonly transmitted signals through ERK activation that required prior phosphorylation of tyrosine 925, but not tyrosine 577, on FAK. Moreover, the inhibition of ERK activation by selective inhibitor PD98059 and FAK expression by FAK-specific RNA interference could significantly abolish the stimulatory effects induced by PGN, flagellin and R837. Taken together, our findings indicate the involvement of FAK-dependent activation of ERK1 in TLR-mediated eosinophil stimulation. A potential role of eosinophils was also suggested in exacerbating allergic inflammation in response to microbial infections.
Keywords: adhesion molecule, chemotaxis, eosinophils, signaling molecules, Toll-like receptor
* These authors contribute equally to this study.
Transmitting editor: D. Tarlinton
Received 4 April 2007, accepted 12 December 2007.