SummaryToxoflasma gondii tachyzoites markedly alter the profile of eicosanoids released by human mononuclear phagocytes. Freshly isolated, 2-h adherent human monocytes release both cyclooxygenase (e.g., thromboxane [TX] B2, prostaglandin [PG] E2) and 5-1ipoxygenase (e.g., leukotriene [LT] ]]4, LTC4) products of arachidonic acid metabolism after stimulation by the calcium ionophore A23187 or ingestion of opsonized zymosan particles or heat-killed T. gondii. However, after incubation with viable T. gondii, normal and chronic granulomatous disease monocytes release only the cyclooxygenase products TXB2 and PGE2 and fail to form LTB4, LTC4, or other 5-1ipoxy-genase products. Monocytes maintained in culture for 5 d lose this capacity to release TXB2 and PGE2 after incubation with T. gondii. T. gondii significantly inhibit calcium ionophore A23187-induced LTB4 release by monocyte-derived macrophages; heat-killed organisms do not affect this calcium ionophore A23187-induced release of LTB4. T. gondii-induced inhibition of LTB4 release by calcium ionophore A23187-stimulated monocyte-derived macrophages is reversed by interferon (IFN)-3' treatment of the monolayers. LTB4 induced extensive damage to the cellular membranes and cytoplasmic contents of the organisms as observed by transmission electron microscopy. Exogenous LTB4 (10-6 M) induced intracellular killing of ingested T. gondii by non-IFN-q,-treated monocyte-derived macrophages. IFN-y-induced antitoxoplasma activity in monocyte-derived macrophages was inhibited by the selective 5-1ipoxygenase inhibitor zileuton but not by the cyclooxygenase inhibitor indomethacin. These findings suggest a novel role for 5-1ipoxygenase arachidonic acid products in human macrophage IFN-3,-induced antitoxoplasma activity.H uman monocytes, but not monocyte-derived macrophages, are cytotoxic to Toxoplasma gondii, an obligate intracellular protozoal parasite (1-3). Monocytes possess a granule peroxidase identical to myeloperoxidase (MPO) 1 of neutrophils and respond to stimulation with a respiratory burst leading to the formation of superoxide anion (Of) and hydrogen peroxide (H202) (4). Monocytes derived from peripheral blood and maintained as adherent cells in culture undergo a variety of biochemical and morphologic changes and differentiate into cells resembling tissue macrophages (5-7). During this transformation in culture, there is a progressive loss of the granule peroxidase (5, 8); after an initial rise at day 3, H202 release also greatly decreases (9). Treatment of 1 Abbreviations used in this paper: CGD, chronic granulomatous disease; HETE, hydroxyeicosatetraenoic acid; IFA, indirect fluorescence antibody; LT, leukotriene; MPO, myeloperoxidase; TX, thromboxane. monocyte-derived macrophages with IFN-3, results in their activation with a concomitant increase in H202 generation when stimulated (7,10).The capacity to generate oxygen radicals and the presence of MPO has been correlated with the antiprotozoal activity of phagocytes (2,11,12). Neutrophils and freshly isolated peroxi...