Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae.
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.
Goodridge
H S
HS
Department of Immunology and Bacteriology, University of Glasgow, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, United Kingdom.
Wilson
E H
EH
Harnett
W
W
Campbell
C C
CC
Harnett
M M
MM
Liew
F Y
FY
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
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