Trypanosoma cruzi (T. cruzi) infection produces an intense inflammatory response which is critical for the control of the evolution of Chagas’ disease. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines identified as modulator of the inflammatory reaction. This work shows that exogenous addition of IL-10 inhibited ERK1/2 and NF-κB activation and reduced inducible nitric oxide synthase (NOS2), metalloprotease (MMP) -9 and MMP-2 expression and activities, as well as tumour necrosis factor (TNF)-α and interleukin (IL)-6 expression, in T. cruzi-infected cardiomyocytes. We found that T. cruzi and IL-10 promote STAT3 phosphorylation and up-regulate the expression of suppressor of cytokine signalling (SOCS)-3 thereby preventing NF-κB nuclear translocation and ERK1/2 phosphorylation. Specific knockdown of SOCS-3 by small interfering RNA (siRNA) impeded the IL-10-mediated inhibition of NF-κB and ERK1/2 activation. As a result, the levels of studied pro-inflammatory mediators were restored in infected cardiomyocytes. Our study reports the first evidence that T. cruzi up- regulates SOCS-3 expression and highlights the relevance of IL-10 in the modulation of pro-inflammatory response of cardiomyocytes in Chagas’ disease.

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Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas' disease, causes cardiac alterations in the host. Although the main clinical manifestations arise during the chronic stage, the mechanisms leading to heart damage develop early during infection. In fact, an intense inflammatory response is observed from acute stage of infection. Recently, peroxisome proliferator-activated receptors (PPARs) have attracted research interest due to their participation in the modulation of inflammation. In this work we addressed the role of 15-Deoxy-∆(12,14) ProstaglandinJ2 (15dPGJ2), a PPARγ natural ligand in the regulation of inflammatory mediators, in acute and chronic experimental mouse models of Chagas' disease with the RA and K98 T. cruzi strains, respectively. This work demonstrates that 15dPGJ2 treatment inhibits the expression and activity of inducible nitric oxide synthase (NOS2) as well as TNF-α and IL-6 mRNA levels. Also, expression and activity of metalloproteinases 2 (MMP-2) and 9 (MMP9) were inhibited by 15dPGJ2. Moreover GW9662, a specific PPARγ antagonist, revealed the participation of other signaling pathways since, in GW9662 presence, 15dPJG2 had a partial effect on the inhibition of inflammatory parameters in the acute model of infection. Accordingly, NF-κB activation was demonstrated, assessing p65 nuclear translocation in the hearts of infected mice with both T. cruzi strains. Such effect was inhibited after 15dPGJ2 treatment. Our findings support the concept that in vivo PPARγ and NF-κB pathways are implicated in the inhibitory effects of 15dPGJ2 on inflammatory mediators at different times depending on whether the infection is caused by the lethal or non-lethal T. cruzi strain.