The microbicidal activity of interferon‐γ‐treated macrophages against Trypanosoma cruzi involves an L‐arginine‐dependent, nitrogen oxide‐mediated mechanism inhibitable by interleukin‐10 and transforming growth factor‐β

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Abstract
The present study was carried out to determine the effector mechanism of anti‐Trypanosoma cruzi activity by interferon (IFN)‐γ plus lipopolysaccharide (LPS)‐treated macrophages. A macrophage cell line (IC‐21) that failed to mount an appreciable oxidative burst was nevertheless found able to control T. cruzi growth after exposure to IFN‐γ alone or IFN‐γ plus LPS. Moreover, microbicidal functions of both inflammatory macrophages and IC‐21 against T. cruzi was found to be inhibited in the presence of NG‐monomethyl‐L‐arginine (NGMMA), a competitive inhibitor of L‐arginine. Addition of supplemental L‐arginine to the culture overcame the capacity of NGMMA to block activated macrophage anti‐T. cruzi functions. The ability of NGMMA to reverse both parasite growth inhibition and killing by IFN‐γ plus LPS‐activated macrophages was found to correlate with the suppression of nitrite accumulation in the culture supernatants. Together, these results implicate the L‐arginine‐dependent production of nitric oxide in T. cruzi killing by activated macrophages. We also tested the ability of interleukin(IL)‐10 and transforming growth factor (TGF)‐β, to block regulation of T. cruzi growth in this system. Both IL‐10 and TGF‐β inhibited anti‐parasite function by IFN‐γ‐activated macrophages, with an optimal dose of 100 units/ml and 0.5 ng/ml, respectively. Moreover, when used in combination, suboptimal doses of IL‐10 and TGF‐β were found to produce a synergistic inhibitory effect in the regulation of T. cruzi growth. The ability of IL‐10 and TGF‐β to suppress microbicidal function was also positively correlated with inhibition of nitrite generation in macrophage culture supernatants. These results predict an in vivo role for IL‐10 and TGF‐β in promoting parasite survival in the face of the host cell‐mediated immune response.