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Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine (PC)-containing secreted product, ES-62

Goodridge, Helen S. and Marshall, Fraser A. and Else, Kathryn J. and Houston, Katrina M. and Egan, Caitlin and Al-Riyami, Lamyaa and Liew, Foo-Yew and Harnett, William and Harnett, Margaret M. (2005) Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine (PC)-containing secreted product, ES-62. Journal of Immunology, 174. pp. 284-293. ISSN 0022-1767

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Abstract

Filarial nematodes, parasites of vertebrates, including humans, secrete immunomodulatory molecules into the host environment. We have previously demonstrated that one such molecule, the phosphorylcholine-containing glycoprotein ES-62, acts to bias the immune response toward an anti-inflammatory/Th2 phenotype that is conducive to both worm survival and host health. For example, although ES-62 initially induces macrophages to produce low levels of IL-12 and TNF-{alpha}, exposure to the parasite product ultimately renders the cells unable to produce these cytokines in response to classic stimulators such as LPS/IFN-{gamma}. We have investigated the possibility that a TLR is involved in the recognition of ES-62 by target cells, because phosphorylcholine, a common pathogen-associated molecular pattern, appears to be responsible for many of the immunomodulatory properties of ES-62. We now demonstrate that ES-62-mediated, low level IL-12 and TNF-{alpha} production by macrophages and dendritic cells is abrogated in MyD88 and TLR4, but not TLR2, knockout, mice implicating TLR4 in the recognition of ES-62 by these cells and MyD88 in the transduction of the resulting intracellular signals. We also show that ES-62 inhibits IL-12 induction by TLR ligands other than LPS, bacterial lipopeptide (TLR2) and CpG (TLR9), via this TLR4-dependent pathway. Surprisingly, macrophages and dendritic cells from LPS-unresponsive, TLR4-mutant C3H/HeJ mice respond normally to ES-62. This is the first report to demonstrate that modulation of cytokine responses by a pathogen product can be abrogated in cells derived from TLR4 knockout, but not C3H/HeJ mice, suggesting the existence of a novel mechanism of TLR4-mediated immunomodulation.

Item type: Article
ID code: 5486
Keywords: immunology, biomedical sciences, pharmacology, infection, disease, Public health. Hygiene. Preventive Medicine, Immunology
Subjects: Medicine > Public aspects of medicine > Public health. Hygiene. Preventive Medicine
Science > Microbiology > Immunology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Professional Services > Information Services
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 13 Feb 2008
    Last modified: 06 Dec 2013 18:34
    URI: http://strathprints.strath.ac.uk/id/eprint/5486

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