EXPERIMENTALPARASITOLOGY

75, 353-360(1992)

Nitric Oxide-Mediated gambiense

Cytostatic Activity on Trypanosoma and Trypanosoma brucei brucei

brucei

PHILLIPPE VINCENDEAU,* SYLVIE DAULOU&DE,* BERNARD VEYRET,? MARIELAURE DARDE,$ BERNARD BOUTEILLE,SANDJEAN LOUPLEMESRE§ *Laboratoire de Parasitologic, Universite de Bordeaux II, Bat 3A 3eme etage, 146 rue Leo saignat, 33076 Bordeaux CCdex, France; fLaboratoire de Photophysique et Photochimie Mokulaire, URA 348 CNRS, Universite de Bordeaux I, 33405 Talence CCdex, France; #Laboratoire de Parasitologic, Fact& de Medecine, 87025 Limoges, France; and §Laboratoire des grandes endemies tropicales, ORSTOM, BP 5045, 34032 Montpellier Cedex 1, France VINCENDEALJ, P., DAULOU~DE, S.,VEYRET, B., DARDE, M.L.,BOUTEILLE, B., AND LEMESRE, J. L. 1992. Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei. Experimental Parasitology 75, 353-360. Macrophages collected from BCG-infected mice or exposed in vitro to interferon-y plus lipopolysaccharide developed a cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei. This trypanostatic activity of activated macrophages was inhibited

by addition of N-monomethyl-L-arginine, an inhibitor of the L-arginine-nitric oxide (NO) metabolic pathway, indicating a role for NO as the effector molecule. Contrary to trypanosomes treated with N, gas, trypanosomes treated with NO gas did not proliferate in vitro on normal macrophages. Compared to mice infected with control parasites, mice infected with NO-treated parasites had decreased parasitemias in the first days postinfection and had a prolonged survival. Addition of excess iron reversed the trypanostatic effect of both activated macrophages and NO gas. These data show that activated macrophages exert an antimicrobial effect on T.b. gambiense and T.6. brucei through the L-arginine-NO metabolic pathway. In trypanosomes, NO could trigger iron loss from critical targets involved in parasite division. The participation of this effector mechanism among the other immune elements involved in the control of African trypanosomes (antibodies, complement, phagocytic events) remains to be defined. 8 wz Academic press, I~C. INDEX DESCRIPTORS AND ABBREVIATIONS: soma brucei brucei; Macrophages; Nitric

Trypanosoma

brucei

gambiense;

Trypano-

oxide; Macrophage cytostatic activity; Macrophage (M@); Bacillus calmette guerin (BCG); NG mono methyl-L-arginine (NMMA); Interferon-y (IFN-y); Lipopolysaccharide (LPS); Tumor necrosis factor-a (TNF-a); Nitric oxide (NO); Nitrite (NO;); Nitrate (NO;); Nitrogen (N,); Transforming growth factor-p (TGFg); Interleukin-4 (IL-4); Interleukin-10 (IL-IO); Deoxyribonucleic acid (DNA); Adenosine triphosphate (ATP).

INTRODUCTION

1988). Host resistance to microorganisms and tumor cells can be increased by immuTrypanosoma brucei gambiense and Try- nostimulants such as mycobacteria and panosoma brucei rhodesiense, the caus- products derived from mycobacteria that ative agents of human sleeping sickness, mainly act by modifying macrophage funcand T.b. brucei, the causative agent of an- tions (Lederer 1980). Thus, BCG induces imal trypanosomiasis, are tse-tse transmitan increased resistance to trypanosome inted protozoa which multiply extracellularly fection in mice (Murray and Morrison in the bloodstream and lymph and intersti1979). tial fluids of their hosts (Wery et al. 1982; Recently, the characterization of moleOrmerod 1979). Macrophages play a key cules with antitumoral and antimicrobial role in the control of protozoan parasites activities has led to the identification of ni(Blackwell and Alexander 1983; Murray trogen oxides as novel activated macro353

OOl4-4894/92 $5.00 Copyright 6 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

VINCENDEAU

354

phage effector molecules (Hibbs ef al. 1987; Stuehr and Nathan 1989). A novel mammalian biochemical pathway synthesizing nitrogen oxides (nitric oxide (NO), nitrite (NO;), and nitrate (NO

Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei.

Macrophages collected from BCG-infected mice or exposed in vitro to interferon-gamma plus lipopolysaccharide developed a cytostatic activity on Trypan...
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