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 mo lecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein of the rodent filarial nematode Acanthocheilonema vi teae, and has homologues in human filarial nematodes. Previously we have-sh own that ES-62 is exclusively associated with a Th2 Ab response in mice. He re we provide a rationale for this polarized immune response by showing tha t 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 cytok ines IL-6 and TNF-alpha, but not NO. The molecular mechanism underlying the se findings awaits elucidation but, intriguingly, the initial response of m acrophages to ES-62 is to demonstrate a low and transient release of these cytokines before becoming refractory to further release induced by IFN-gamm a /LPS. The relevance of our observations is underscored by the finding tha t macrophages recovered from mice exposed to "physiological" levels of ES-6 2 by the novel approach of continuous release from implanted osmotic pumps in vivo were similarly refractory to release of IL-12, TNF-alpha YL-6, but not NO, ex vivo. Therefore, our results suggest that exposure to ES-62 rend ers macrophages subsequently unable to produce Th1/proinflammatory cytokine s. This likely contributes to the generation of immune responses with an an tiinflammatory Th2 phenotype, a well-documented feature of filarial nematod e infection.