Platelet-activating factor induces nitric oxide synthesis in Trypanosoma cruzi-infected macrophages and mediates resistance to parasite infection in mice.
Trypanosoma cruzi replicates in nucleated cells and is susceptible to being killed by gamma interferon-activated macrophages through a mechanism dependent upon NO biosynthesis. In the present study, the role of platelet-activating factor (PAF) in the induction of NO synthesis and in the activation of the trypanocidal activity of macrophages was investigated. In vitro, PAF induced NO secretion by T. cruzi-infected macrophages and the secreted NO inhibited intracellular parasite growth. The addition of a PAF antagonist, WEB 2170, inhibited both NO biosynthesis and trypanocidal activity. The inducible NO synthase/L-arginine pathway mediated trypanocidal activity, since it was inhibited by treatment with L-N-monomethyl arginine (L-NMMA), an L-arginine analog. PAF-mediated NO production in infected macrophages appears to be dependent on tumor necrosis alpha (TNF-alpha) production, since the addition of a neutralizing anti-TNF-alpha monoclonal antibody mAb inhibited NO synthesis. To test the role of PAF in mediating resistance or susceptibility to T. cruzi infection, infected mice were treated with WEB 2170, a PAF antagonist. These animals had higher parasitemia and earlier mortality than did vehicle-treated mice. Taken together, our results suggest that PAF belongs to a group of mediators that coordinate the mechanisms of resistance to infections with intracellular parasites.
Aliberti
J C
JC
Department of Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, ICB, UFMG, Belo Horizonte, Minas Gerais, Brazil.
Machado
F S
FS
Gazzinelli
R T
RT
Teixeira
M M
MM
Silva
J S
JS
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D008253:Macaca mulatta; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D018512:Parasitemia; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014344:Trypanocidal Agents / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000276:immunology*
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014344:Trypanocidal Agents; C039351:platelet activating factor receptor; D009569:Nitric Oxide