A Role for Parasite-Induced PGE2 in IL-10-Mediated Host Immunoregulation by Skin Stage Schistosomula of Schistosoma mansoni1

Significant quantities of PGE2 were produced by cercariae of Schistosoma mansoni following incubation with linoleic acid, a free fatty acid found on the surface of the skin. Cyclooxygenase (COX) 2 inhibitors failed to block this PGE2 production, suggesting that a different biochemical pathway may be involved in the production of PGE2 by the parasite. In addition, the parasites were also able to induce PGE2 and IL-10 from human and mouse keratinocytes. Analysis of mouse skin during skin migratory phases of infection confirmed these in vitro observations. COX2 inhibitors blocked the parasite-induced PGE2 and IL-10 from keratinocytes. Further analysis of the parasite secretions showed that the PGE2/IL-10-inducing effect was associated with a fraction <30 kDa molecular size. Addition of this fraction or parasite-stimulated keratinocyte culture supernatant to Con A-stimulated spleen cells resulted in the suppression of cell proliferation. This effect could be blocked by anti-IL-10 treatment. In sharp contrast, attenuation of the parasites with γ-irradiation significantly abrogated their ability to induce PGE2 or IL-10 from skin cells. Significance of IL-10 in host immunoregulation by skin stage schistosomula of S. mansoni was further confirmed by using IL-10-deficient mice. In these mice the normal subdued cutaneous reaction to the parasite was absent. Instead, a prominent cellular reaction occurred around the parasite, and there was considerable delay in parasitic migration through the skin. Thus these results suggest a key role for parasite-induced PGE2 in IL-10-dependent down-regulation of host immune responses in the skin.