Alteration of leukotriene release by macrophages ingesting Toxoplasma gondii.

Abstract

Mouse resident peritoneal macrophages incubated with ionophore A23187 or opsonized zymosan released leukotrienes (LT) B4 and C4 (LTB4 and LTC4) and LTC4 and LTD4, respectively. In contrast, incubation with Toxoplasma gondii, an obligate intracellular protozoan, led to the formation of 11-, 12-, and 15-hydroxyicosatetraenoic acids (HETEs), together with an unidentified compound, designated compound X. Each of these compounds incorporated [3H]arachidonic acid from the macrophage during phagocytosis of T. gondi. Compound X migrated immediately prior to 15-HETE by reversephase HPLC and was distinct from authentic monoHETE, monohydroperoxyicosatetraenoic acid (mono-HPETE), and dihydroxyicosatetraenoic acid (diHETE) standards. The generation of compound X by macrophages correlated with the extent of phagocytosis of T. gondii and with intracellular survival of the organisms. Prior antibody-coating of T. gondii or activation of macrophages, either of which inhibited survival and replication of ingested organisms, was associated with production of LTD4 but not compound X. Killed organisms also stimulated LTD4 release only. Although T. gondii concentrated arachidonic acid, they did not metabolize the compound to identifiable lipoxygenase products. Preincubation of macrophages with the relative lipoxygenase inhibitors nordihydroguaiaretic acid or 5,8,11,14-icosatetraynoic acid inhibited the formation of compound X. The absence of leukotriene production by macrophages ingesting T. gondji may explain the relative lack of a neutrophil inflammatory response in diseases due to obligate intracellular organisms. Alternatively, compound X may have functional activities that might mediate some of the host responses to cellular parasitism.The leukotrienes (LT) have been identified as potentially important inflammatory mediators of host defense (1, 2). LTB4 is a potent neutrophil chemoattractant and stimulus for aggregation, degranulation, and adherence to endothelium. The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4, which collectively constitute the slow-reacting substance of anaphylaxis (SRS), promote vasoconstriction and enhance permeability across the postcapillary venule. Resident tissue macrophages are major sources of the LT (3-5). The plasma membrane of these cells is rich in esterified arachidonate that is released during membrane perturbation and is then available to Ca2+-dependent 5-lipoxygenase that regulates the formation of the LT (6, 7). Traditional stimuli for LT production by macrophages in vitro include both soluble (calcium ionophore A23187, endotoxin, phorbol myristate acetate) and particulate (zymosan, immunocomplexes) stimuli; LT production in response to the latter has been related directly to the degree of phagocytosis (3-5).Resident tissue macrophages are the initial target of many obligate intracellular pathogens that infect man, but the capacity of viable organisms to trigger the release of inflammatory mediators from macrophages has not been systematically investigated. The pathogenic protozoa...

Candida albicans induces the release of inflammatory mediators from human peripheral blood monocytes

“…Our data indicates that peripheral blood monocytes respond to C. albicans challenge by releasing AA. Prior studies have demonstrated that mononuclear cells release AA in response to a variety of microorganisms including Fusobacterium nucleatum, Gardnerella vaginalis, Peptostreptococcus anaerobius, Histoplasma capsulatum, Mycobacterium intercellulare, Leishmania donovani, and Toxoplasma gondii [39][40][41][42][43]. Additional investigations in our laboratory have similarly indicated that C. albicans also induces alteration in eicosanoid metabolism in alveolar tissue macrophages.…”

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

“…These data are consistent with earlier in vitro reports which indicated that the exposure of macrophages to T. gondii triggers an increase in arachidonic acid release and lipoxygenase activity that largely favors the 12/15-LOX product 12(S)-HETE (37). However, since 12(S)-HETE is the major product of murine 12/15-LOX (24,52), it is possible that the apparently selective nature of the 12/15-LOX-dependent increased 12(S)-HETE production in wild-type mice may be related to the sensitivity of our assay. Also, the increased abundance of this 12/15-LOX product could represent a decrease in metabolism/uptake or an increased proportion of 12/15-LOX-expressing cells rather than an induction of expression or activity in a given cell type.…”

Comparison of Eicosanoids Production between Rat Polymorphonuclear Leukocytes and Macrophages: Detection by High-Performance Liquid Chromatography with Precolumn Fluorescence Labeling.

“…Some reports demonstrated that murine res ident macrophages generate LTB4 when stimulated with A23187 (16)(17)(18) or endotoxin (19), while the metabolites in macrophages are differentially altered by endotoxin tolerance (19) and Listeria immunization (20), suggest ing that macrophages collected from an in flammatory site may have different natures from resident macrophages.…”