Proapoptotic activity of a Trypanosoma cruzi ceramide-containing glycolipid turned on in host macrophages by IFN-gamma.
The effects of glycoinositolphospholipid (GIPL), from the pathogenic protozoan Trypanosoma cruzi, and its isolated glycan and lipid (dihydroceramide) components, were investigated in J774 cells and primary macrophages. Isolated GIPL ceramide, but not intact GIPL or its glycan, induced intense fluid phase endocytosis when added exogenously. In the presence of the cytokine IFN-gamma, GIPL ceramide induced marked apoptosis in J774 cells and macrophages, independent of nitric oxide secretion. When cells were preincubated with the GIPL-derived glycan chain, addition of intact GIPL induced macrophage apoptosis in the presence of IFN-gamma. Synthetic C2-dihydroceramide also induced apoptosis in the presence of IFN-gamma. Induction of apoptosis in T. cruzi-infected macrophages by GIPL ceramide plus IFN-gamma led to increased parasite release compared with IFN-gamma treatment alone. Viable parasites released comprised both infective trypomastigote and spheromastigote forms. These results identify a novel pathway by which T. cruzi glycosylphosphatidylinositol family molecules affect host macrophages, with implications for the infectious process.
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Immunobiology Program, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002518:Ceramides / Q000494:pharmacology; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006017:Glycolipids / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010743:Phospholipids / Q000494:pharmacology*; D011134:Polysaccharides / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000737:chemistry* / Q000276:immunology / Q000472:pathogenicity; D014407:Tumor Cells, Cultured; D014774:Virulence; D019323:omega-N-Methylarginine / Q000494:pharmacology
D002518:Ceramides; D006017:Glycolipids; D008070:Lipopolysaccharides; D010743:Phospholipids; D011134:Polysaccharides; C109343:dihydroceramide; C115336:glycoinositolphospholipid, Trypanosoma; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse