Leukotriene B(4) induces nitric oxide synthesis in Trypanosoma cruzi-infected murine macrophages and mediates resistance to infection.

Abstract

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.

• Authors: A Talvani, F S Machado, G C Santana, A Klein, L Barcelos, J S Silva, M M Teixeira
• Journal: Infection and immunity (Infect Immun) Vol. 70 Issue 8 Pg. 4247-53 (Aug 2002) ISSN: 0019-9567 [Print] United States
• PMID: 12117933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzopyrans
• Carboxylic Acids
• Platelet Activating Factor
• Receptors, Leukotriene B4
• Tumor Necrosis Factor-alpha
• Leukotriene B4
• Nitric Oxide
• Interferon-gamma
• CP 105696

Topics

• Animals
• Benzopyrans (pharmacology)
• Carboxylic Acids (pharmacology)
• Cells, Cultured
• Chagas Disease (immunology)
• Disease Models, Animal
• Female
• Immunity, Innate (immunology)
• Interferon-gamma (immunology)
• Leukotriene B4 (immunology, pharmacology)
• Macrophage Activation (immunology)
• Macrophages, Peritoneal (drug effects, immunology, parasitology)
• Mice
• Mice, Inbred BALB C
• Nitric Oxide (biosynthesis, immunology)
• Platelet Activating Factor (antagonists & inhibitors)
• Receptors, Leukotriene B4 (antagonists & inhibitors)
• Time Factors
• Trypanosoma cruzi (immunology)
• Tumor Necrosis Factor-alpha (immunology)