Leukotriene B(4) induces nitric oxide synthesis in Trypanosoma cruzi-infected murine macrophages and mediates resistance to infection.
The production of nitric oxide (NO) by gamma interferon (IFN-gamma)-activated macrophages is a major effector mechanism during experimental Trypanosoma cruzi infection. In addition to IFN-gamma, chemoattractant molecules, such as platelet-activating factor (PAF) and CC chemokines, may also activate macrophages to induce NO and mediate the killing of T. cruzi in an NO-dependent manner. Here we investigated the ability of leukotriene B(4) (LTB(4)) to induce the production of NO by macrophages infected with T. cruzi in vitro and whether NO mediated LTB(4)-induced parasite killing. The activation of T. cruzi-infected but not naive murine peritoneal macrophages with LTB(4) induced the time- and concentration-dependent production of NO. In addition, low concentrations of LTB(4) acted in synergy with IFN-gamma to induce NO production. The NO produced mediated LTB(4)-induced microbicidal activity in macrophages, as demonstrated by the inhibitory effects of an inducible NO synthase inhibitor. LTB(4)-induced NO production and parasite killing were LTB(4) receptor dependent and were partially blocked by a PAF receptor antagonist. LTB(4) also induced significant tumor necrosis factor alpha (TNF-alpha) production, and blockade of TNF-alpha suppressed LTB(4)-induced NO release and parasite killing. A blockade of LTB(4) or PAF receptors partially inhibited IFN-gamma-induced NO and TNF-alpha production but not parasite killing. Finally, daily treatment of infected mice with CP-105,696 was accompanied by a significantly higher level of blood parasitemia, but not lethality, than that seen in vehicle-treated animals. In conclusion, our results suggest a role for LTB(4) during experimental T. cruzi infection. Chemoattractant molecules such as LTB(4) not only may play a major role in leukocyte migration into sites of inflammation in vivo but also, in the event of an infection, may play a relevant role in the activation of recruited leukocytes to kill the invading microorganism in an NO-dependent manner.
Talvani
A
A
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Machado
F S
FS
Santana
G C
GC
Klein
A
A
Barcelos
L
L
Silva
J S
JS
Teixeira
M M
MM
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology* / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D001578:Benzopyrans; D002264:Carboxylic Acids; D010972:Platelet Activating Factor; D018102:Receptors, Leukotriene B4; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D009569:Nitric Oxide; D007371:Interferon-gamma; C089698:CP 105696