Leishmania chagasi: cytotoxic effect of infected macrophages on parenchymal liver cells.
Leishmania (Leishmania) chagasi, the ethiological agent of New World visceral leishmaniasis, causes morphological and functional injury to the liver. To investigate the role of macrophage-released leishmanicidal factors in hepatocyte damage, we used a co-culture model of hepatocytes and L. chagasi promastigote-infected peritoneal macrophages obtained from C57BL/6 or BALB/c mice. C57BL/6 macrophages killed intracellular parasites more efficiently than BALB/c macrophages, leading to higher number of intracellular amastigotes in the BALB/c culture during the entire course of infection. Early TNF-alpha production led to macrophages activation resulting in parasite growth control. Hepatic transaminases and lactate dehydrogenase were present at high levels in the supernatants of both co-cultures; concurrently, parasites were eliminated from infected macrophages. Nitric oxide production was higher in C57BL/6 co-cultures than in BALB/c co-cultures. Inhibitors of the oxidative burst and secreted proteinases protected hepatocytes against toxicity, and treatment with an inducible nitric oxide synthase inhibitor fully impeded the enzyme release. Our data suggest that the intracellular cytotoxic effects elicited by macrophages for parasite destruction are directly associated with hepatocyte damage, and that nitric oxide plays a pivotal role in this phenomenon.
Dias Costa
Juliana
J
Laboratório de Pesquisas em Leishmaniose, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil 4365, Rio de Janeiro, RJ 21045-900, Brazil.
de Nazareth Meirelles
Maria
M
Eduardo Pereira Velloso
Carlos
C
Porrozzi
Renato
R
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D018920:Coculture Techniques; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018314:Leishmania infantum / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology* / Q000648:ultrastructure; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009569:Nitric Oxide / Q000378:metabolism; D011247:Pregnancy
D016207:Cytokines; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase