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Infection and Immunity, August 2002, p. 4247-4253, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4247-4253.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Leukotriene B4 Induces Nitric Oxide Synthesis in Trypanosoma cruzi-Infected Murine Macrophages and Mediates Resistance to Infection

A. Talvani,1 F. S. Machado,2 G. C. Santana,1 A. Klein,1,{dagger} L. Barcelos,1 J. S. Silva,2 and M. M. Teixeira1*

Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais,1 Departamento de Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil2

Received 9 October 2001/ Returned for modification 7 December 2001/ Accepted 15 April 2002

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 B4 (LTB4) to induce the production of NO by macrophages infected with T. cruzi in vitro and whether NO mediated LTB4-induced parasite killing. The activation of T. cruzi-infected but not naive murine peritoneal macrophages with LTB4 induced the time- and concentration-dependent production of NO. In addition, low concentrations of LTB4 acted in synergy with IFN-{gamma} to induce NO production. The NO produced mediated LTB4-induced microbicidal activity in macrophages, as demonstrated by the inhibitory effects of an inducible NO synthase inhibitor. LTB4-induced NO production and parasite killing were LTB4 receptor dependent and were partially blocked by a PAF receptor antagonist. LTB4 also induced significant tumor necrosis factor alpha (TNF-{alpha}) production, and blockade of TNF-{alpha} suppressed LTB4-induced NO release and parasite killing. A blockade of LTB4 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 LTB4 during experimental T. cruzi infection. Chemoattractant molecules such as LTB4 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.

* Corresponding author. Mailing address: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627-Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Phone: 55 31 3499 2651. Fax: 55 31 3441 5963. E-mail: mmtex{at}icb.ufmg.br.

Editor: S. H. E. Kaufmann

{dagger} Present address: Imunofarmacologia, Departamento de Morfofisiologia, Centro de Ciencias Biologicas, Universidade Federal de Mato Grosso do Sul, 79070-900 Campo Grande, Mato Grosso do Sul, Brazil.

Infection and Immunity, August 2002, p. 4247-4253, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4247-4253.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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