TOXOPLASMA-GONDII ALTERS EICOSANOID RELEASE BY HUMAN MONONUCLEAR PHAGOCYTES - ROLE OF LEUKOTRIENES IN INTERFERON-GAMMA-INDUCED ANTITOXOPLASMA ACTIVITY

Toxoplasma 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] B-2, prostaglandin [PG] E(2)) and 5-lipoxygenase (e.g., leukotriene [LT] B-4, LTC(4)) 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 TXB(2) and PGE(2) and fail to form LTB(4), LTC(4), or other 5-lipoxygenase products. Monocytes maintained in culture for 5 d lose this capacity to release TXB(2) and PGE(2) after incubation with T. gondii. T. gondii significantly inhibit calcium ionophore A23187-induced LTB(4) release by monocyte-derived macrophages; heat-killed organisms do not affect this calcium ionophore A23187-induced release of LTB(4). T. gondii-induced inhibition of LTB(4) release by calcium ionophore A23187-stimulated monocyte-derived macrophages is reversed by interferon (IFN)-gamma treatment of the monolayers. LTB(4) induced extensive damage to the cellular membranes and cytoplasmic contents of the organisms as observed by transmission electron microscopy. Exogenous LTB(4) (10(-6) M) induced intracellular killing of ingested T. gondii by non-IFN-gamma-treated monocyte-derived macrophages. IFN-gamma-induced antitoxoplasma activity in monocyte-derived macrophages was inhibited by the selective 5-lipoxygenase inhibitor zileuton but not by the cyclooxygenase inhibitor indomethacin. These findings suggest a novel role for 5-lipoxygenase arachidonic acid products in human macrophage IFN-gamma-induced antitoxoplasma activity.