INVESTIGADORES
AOKI Maria Del Pilar
congresos y reuniones científicas
Título:
The protozoan parasite Trypanosoma cruzi modulates the activation of IL-6/STAT-3 signaling pathway through gp130 cleavage: impact on different cell types
Autor/es:
AOKI MP
Reunión:
Simposio; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2013
Resumen:
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.