Toxoplasma gondii alters eicosanoid release by human mononuclear phagocytes: role of leukotrienes in interferon gamma-induced antitoxoplasma activity.

Abstract

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...

Leukotrienes Are Essential for the Control ofLeishmania amazonensisInfection and Contribute to Strain Variation in Susceptibility

“…Wirth et al (11,12) reported that both LTB 4 and LTC 4 increased the phagocytosis and killing of Trypanosoma cruzi by peritoneal macrophages. The IFN-␥-mediated killing of Toxoplasma gondii by human monocytes was shown to be dependent on LT biosynthesis (13). In addition, Talvani et al (14) showed that during T. cruzi infection, LTB 4 is able to promote NO release and thereby kill this parasite.…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…The cells degranulate and release LTB4, which damage tachyzoites [625] . Earlier study showed that LTB4-induced T. gondii cytotoxicity was characterized by vesiculation of the surface membrane and loss of the cytoplasmic contents of the organisms [624] , and the same cytotoxic changes were observed in tachyzoites after incubation with MCs [625] . Although the parasite inhibited mast cell degranulation by suppressing the mobilization of intracellular Ca 2+ mediated by C-phospholipase [630] , many biomediators, such as IL-6, can also be released from mast cells "selectively", without degranulation [631,632] .…”

“…Effector cells against T. gondii include monocytes [617] , IFN-γ-activated macrophages [420,624] , neutrophils [623] , and platelets [417] . MCs also participate in host defense against the parasite .…”

Requirement of JNK-Mediated Phosphorylation for Translocation of Group IVA Phospholipase A2 to Phagosomes in Human Macrophages

“…Mice lacking cPLA 2 ␣ manifest a reduced clearance of bacteria in vivo (12), which is also the case for 5-lipoxygenase-deficient mice (5). It has been suggested that leukotrienes enhance microbicidal activity in macrophages by activating the NADPH oxidase (2,3,54). Thus, an argument has been made in favor of a therapeutic use of receptor agonists capable of activating cPLA 2 ␣ such as ATP in combination with other antimicrobial drugs to efficaciously treat complex infections (13,(55)(56)(57).…”

“…In addition to their demonstrated pro and antiinflammatory properties, phagocyte-derived eicosanoids have been implicated in the control of infections. In in vitro and in vivo models, the eicosanoids have been shown to modulate the microbicidal activity of phagocytes (1)(2)(3)(4)(5).…”