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Published ahead of print on March 1, 2007, doi:10.1165/rcmb.2006-0457OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 85-96, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0457OC

Intracellular Signaling Mechanisms Regulating Toll-Like Receptor–Mediated Activation of Eosinophils

Chun K. Wong, Phyllis F. Y. Cheung, Wai K. Ip and Christopher W. K. Lam

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong; and the Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau

Correspondence and requests for reprints should be addressed to Professor C. W. K. Lam, Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong. E-mail: waikeilam{at}cuhk.edu.hk

Activation of eosinophils by microbe-derived molecules via Toll-like receptors (TLR) potentially provides the link between microbe-induced innate immune responses and the exacerbation of allergic inflammation. We investigated the expression of TLRs and the effect of their ligands on human eosinophils. Expression of TLR1–9 was detected by Western blot and flow cytometry. Adhesion molecules, cytokines, superoxides, and eosinophlilic cationic protein (ECP) were assessed by flow cytometry, enzyme-linked immunosorbent assay, chemiluminescent method, and fluorescence immunoassay, respectively. Human eosinophils differentially expressed TLR1, -2, -4, -5, -6, -7, and -9. Peptidoglycan (PGN) (TLR2 ligand), flagellin (TLR5 ligand), and Imiquimod R837 (TLR7 ligand) could significantly upregulate cell surface expression of intercellular adhesion molecule (ICAM)-1 and CD18, and induce the release of IL-1beta, IL-6, IL-8, growth-related oncogene (GRO)-{alpha}, and superoxides of eosinophils. Only PGN could induce the degranulation for ECP release. However, ds poly I-C (TLR3 ligand), LPS (TLR4 ligand), ssRNA (TLR8 ligand), and CpG-DNA (TLR9 ligand) were much less effective or inactive. PGN, flagellin, and R837 could activate both nuclear factor (NF)-{kappa}B and extracellular signal–regulated protein kinase (ERK). PGN could activate phosphatidylinositol 3-kinase (PI3K)-Akt, and R837 both PI3K-Akt and p38 mitogen-activated protein kinase (MAPK). The induction of the release of IL-1beta, IL-6, IL-8, GRO-{alpha}, superoxides, and ECP by PGN, flagellin, and R837 was found to be differentially regulated by NF-{kappa}B, ERK, PI3K-Akt, and p38 MAPK. The above results therefore support that microbial infection may lead to the exacerbation of allergic inflammation.

Key Words: Toll-like receptors • eosinophils • cytokines • chemokines • signal transduction


CLINICAL RELEVANCE

Results demonstrate the intracellular mechanisms for the Toll-like receptor–mediated activation of eosinophils, thereby providing new postulates for immunopathologic mechanisms and drug development of respiratory tract infection–mediating allergic inflammation.

 



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