title: Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae.
abstract: Parasite survival and host health may depend on the ability of the parasite to modulate the host immune response by the release of immunomodulatory molecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein of the rodent filarial nematode Acanthocheilonema viteae, and has homologues in human filarial nematodes. Previously we have shown that ES-62 is exclusively associated with a Th2 Ab response in mice. Here we provide a rationale for this polarized immune response by showing that the parasite molecule suppresses the IFN-gamma/LPS-induced production, by macrophages, of bioactive IL-12 (p70), a key cytokine in the development of Th1 responses. This suppression of the induction of a component of the host immune response extends to the production of the proinflammatory cytokines IL-6 and TNF-alpha, but not NO. The molecular mechanism underlying these findings awaits elucidation but, intriguingly, the initial response of macrophages to ES-62 is to demonstrate a low and transient release of these cytokines before becoming refractory to further release induced by IFN-gamma/LPS. The relevance of our observations is underscored by the finding that macrophages recovered from mice exposed to "physiological" levels of ES-62 by the novel approach of continuous release from implanted osmotic pumps in vivo were similarly refractory to release of IL-12, TNF-alpha, IL-6, but not NO, ex vivo. Therefore, our results suggest that exposure to ES-62 renders macrophages subsequently unable to produce Th1/proinflammatory cytokines. This likely contributes to the generation of immune responses with an anti-inflammatory Th2 phenotype, a well-documented feature of filarial nematode infection.
authors: Department of Immunology and Bacteriology, University of Glasgow, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, United Kingdom.
authors: H S
authors: HS
authors: Goodridge
authors: E H
authors: EH
authors: Wilson
authors: W
authors: W
authors: Harnett
authors: C C
authors: CC
authors: Campbell
authors: M M
authors: MM
authors: Harnett
authors: F Y
authors: FY
authors: Liew
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004153:Dipetalonema / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D006023:Glycoproteins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D015801:Helminth Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004338:Drug Combinations; D006023:Glycoproteins; D015801:Helminth Proteins; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D018664:Interleukin-12; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C435884:ES-62 protein, Acanthocheilonema viteae