Nitric oxide-induced apoptotic cell death in the acute phase of Trypanosoma cruzi infection in mice.
Production of gamma-interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in Trypanosoma cruzi-infected mice results in the activation of inducible nitric oxide synthase (iNOS) and in elevated nitric oxide (NO) synthesis, which is important for the macrophage trypanocidal activity. However, NO has been shown to be involved in suppression of host immunity. In the present investigation, we studied the role of NO in inducing apoptosis in cells from BALB/c mice acutely infected by T. cruzi. Splenocytes from infected mice had a reduced cell viability and elevated levels of spontaneous apoptosis after 48 h in culture. Inhibition of NO production by the addition of the L-arginine analog NG-monomethyl-L-arginine (L-NMMA), or of monoclonal antibodies (mAbs) to IFN-gamma or TNF-alpha spleen cells, partially restored cell viability and caused a decrease in the levels of apoptosis in splenocytes from infected animals. Spleen cells from T. cruzi-infected mice had an apoptosis-specific pattern of internucleosomal DNA fragmentation which was most marked at the ninth day after infection when the plasma NO levels and parasitemia were increased. Treatment of infected mice with L-NMMA, anti-TNF-alpha, or anti-IFN-gamma mAbs caused reduction of both NO production and the amount of apoptotic cells, suggesting that NO plays a direct role in the induction of apoptosis in vivo. Taken together, these data support the hypothesis that, as well as modulating immunosuppression, NO produced by IFN-gamma and TNF-alpha activated macrophages plays a role in apoptosis induction during the acute phase of experimental T. cruzi infection.
Martins
G A
GA
Department of Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Cardoso
M A
MA
Aliberti
J C
JC
Silva
J S
JS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D014355:Chagas Disease / Q000201:enzymology / Q000473:pathology*; D016054:DNA, Protozoan / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009707:Nucleosomes / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D009707:Nucleosomes; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse