Infection with Trypanosoma cruzi causes a strong inflammatory reaction at the inoculation site and, later, in the myocardium. The present study investigates the role of cytokines as modulators of T. cruziinduced chemokine expression in vivo and in vitro. In macrophage cultures, although the stimulation with interferon (IFN)-g increases the expression of IP-10, it blocks KC expression. Tumor necrosis factor (TNF)-a, on the other hand, potentiates KC, IP-10, macrophage inflammatory protein-1a, and JE/monocyte chemotatic protein-1 expression. Interleukin-10 and transforming growth factor-b inhibited almost all chemokines tested. The role of IFN-g and TNF-a in chemokine modulation during infection was investigated in T. cruzi-infected IFN-g-deficient (GKO) or TNFR1/ p55-deficient (p552/2) mice. The expression of chemokines detected in the inoculation site correlated with the infiltrating cell type observed. Although GKO mice had a delayed and intense neutrophilic infiltrate correlating with the expression of KC and macrophage inflammatory protein-2, none of the above was observed in p552/2 mice. The detection of infiltrating T cells, Mig, and IP-10 in the myocardium was observed in wild-type and p552/2, but not in GKO mice. Together, these results suggest that the regulatory roles of IFN-g and TNF-a on chemokine expression may play a crucial role in the modulation of the inflammatory response during T. cruzi infection and mediate resistance to infection.