title: Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62.
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.
authors.affiliation: Division of Immunology, Infection, and Inflammation, University of Glasgow, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, Scotland, UK.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
authors.forename: Fraser A
authors.initials: FA
authors.lastname: Marshall
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Else
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Houston
authors.forename: Caitlin
authors.initials: C
authors.lastname: Egan
authors.forename: Lamyaa
authors.initials: L
authors.lastname: Al-Riyami
authors.forename: Foo-Yew
authors.initials: FY
authors.lastname: Liew
authors.forename: William
authors.initials: W
authors.lastname: Harnett
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005370:Filarioidea / Q000276:immunology; D005434:Flow Cytometry; D015801:Helminth Proteins / Q000276:immunology* / Q000378:metabolism; D007155:Immunologic Factors; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015801:Helminth Proteins; D007155:Immunologic Factors; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein; C507780:Myd88 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse