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

Helen S. Goodridge, Fraser A. Marshall, Kathryn J. Else, Katrina M. Houston, Caitlin Egan, Lamyaa Al-Riyami, Foo-Yew Liew, William Harnett, Margaret M. Harnett

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178 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)284-293
Number of pages9
JournalJournal of Immunology
Volume174
Publication statusPublished - Jan 2005

Keywords

  • immunology
  • biomedical sciences
  • pharmacology
  • infection
  • disease

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    Goodridge, H. S., Marshall, F. A., Else, K. J., Houston, K. M., Egan, C., Al-Riyami, L., ... Harnett, M. M. (2005). Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine (PC)-containing secreted product, ES-62. Journal of Immunology, 174, 284-293.