(Circulation. 2000;102:3003.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Trypanosoma cruzi–Infected Cardiomyocytes Produce Chemokines and Cytokines That Trigger Potent Nitric Oxide–Dependent Trypanocidal Activity
From the Departments of Immunology (F.S.M., G.A.M., J.C.S.A., J.S.S.) and Pharmacology (F.L.A.C.M., F.Q.C.), School of Medicine-USP, Ribeirão Preto, SP, Brazil.
Correspondence to Dr João S. Silva, Department of Immunology, School of Medicine-USP, Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil. E-mail jsdsilva{at}fmrp.usp.br
Background—The pathogenesis of myocarditis that occurs in Trypanosoma cruzi–infected mice is still poorly understood. Therefore, it is important to know the mediators that trigger leukocyte migration to the heart as well as the cellular source of these possible mediators. In this study, we investigated (1) NO synthase (NOS) induction, (2) NO synthesis, (3) trypanocidal activity, and (4) chemokine and cytokine mRNA expression by isolated cardiomyocytes infected with T cruzi.
Methods and Results—Mouse cardiomyocytes were
isolated, infected with T cruzi, and evaluated for
induction of inducible NOS (iNOS), nitrite production,
trypanocidal activity, and cytokine and chemokine mRNA
expression. We found that T cruzi–infected murine
embryonic cardiomyocytes produced nitrite and expressed
mRNAs for the chemokines chemokine growth-related oncogene,
monokine induced by interferon-
, macrophage inflammatory
protein-2, interferon-–inducible protein, RANTES, and monocyte
chemotactic protein, for iNOS, and for the cytokines tumor
necrosis factor (TNF)-
and interleukin (IL)-1ß. Separate addition
of IL-1ß, interferon-, TNF- or monocyte chemotactic protein,
macrophage inflammatory protein-2, and
interferon-–inducible protein, to cultured
cardiomyocytes resulted in NO production but low
trypanocidal activity. However, simultaneous addition of
IL-1ß, interferon-, and TNF- or the chemokines to cultures
resulted in the induction of iNOS, high levels of nitrite, and a marked
trypanocidal activity. The iNOS/L-arginine pathway mediated
the latter activity, inasmuch as it was inhibited by treatment with
NG-monomethyl-L-arginine.
Conclusions—These results indicate that iNOS activation and the proinflammatory cytokines and chemokines produced by cardiomyocytes are likely to control parasite growth and cell influx, thus contributing to the pathogenesis of chagasic cardiomyopathy seen in T cruzi–infected mice.
Key Words: heart diseases • myocarditis • myocytes • interleukins • nitric oxide
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