The protozoan parasite Trypanosoma cruzi modulates the activation of IL-6/STAT-3 signaling pathway through gp130 cleavage: impact on different cell types

AOKI MP

Simposio; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Cell death is expected to occur as a last resort in immune defense to pathogens and accordingly must be tightly regulated. In this regard, interleukine-6 (IL-6) mediates host defense and cell survival mainly through the activation of the transcription factor STAT3 via the glycoprotein gp130, a shared signal-transducing receptor for several IL-6 family members. We have reported that the cardiotropic parasite Trypanosoma cruzi, the etiological agent of Chagas disease, protects murine cardiomyocytes from apoptosis. Here we report that inactive cruzipain, the main cysteine protease secreted by the parasite, specifically triggers toll like receptor-2 and the subsequent release of IL-6, which acts as an essential anti-apoptotic factor for cardiomyocyte cultures. Although comparable IL-6 levels are release under active cruzipain stimulation, starved cardiac cell monolayers cannot be rescue from apoptosis. Moreover, treatment with active cruzipain completely abrogates the STAT3 phosphorylation and nuclear translocation induced by recombinant IL-6 in cardiomyocytes. The IL-6/STAT3 pathway inhibition is also observed in murine splenocytes, but it is reverted when the enzyme is complexed with its parasite inhibitor. Furthermore, pre-activated cysteine proteases present in trypomastigote supernatants, reduce the TGF-b/IL-6-induced CD4+IL17+ cells in splenocytes subjected to Th17 polarizing conditions. To account for these observations, we found that cruzipain enzymatically cleaves recombinant gp130 ectodomain, and induces the release of membrane-distal N-terminal domain of this receptor on human peripheral blood mononuclear cells. These results strongly suggest that the parasite may modify the IL-6-induced response through the modulation of its cysteine protease activity on different cell types.