title: Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells.
abstract: Interleukin-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-type cytokines. We have reported that the cardiotrophic parasite Trypanosoma cruzi protects murine cardiomyocytes from apoptosis. In agreement, an intense induction of the anti-apoptotic factor Bcl-2 is found in cardiac fibers during the acute phase of infection, establishing a higher threshold against apoptosis. We report here that inactive cruzipain, the main cysteine protease secreted by the parasite, specifically triggered TLR2 and the subsequent release of IL-6, which acted as an essential anti-apoptotic factor for cardiomyocyte cultures. Although comparable IL-6 levels were found under active cruzipain stimulation, starved cardiac cell monolayers could not be rescued from apoptosis. Moreover, cardiomyocytes treated with active cruzipain completely abrogated the STAT3 phosphorylation and nuclear translocation induced by recombinant IL-6. This inhibition was also observed on splenocytes, but it was reverted when the enzyme was complexed with chagasin, a parasite cysteine protease inhibitor. Furthermore, the inhibition of IL-6-induced p-STAT3 was evidenced in spleen cells stimulated with pre-activated supernatants derived from trypomastigotes. To account for these observations, we found that cruzipain enzymatically cleaved recombinant gp130 ectodomain, and induced the release of membrane-distal N-terminal domain of this receptor on human peripheral blood mononuclear cells. These results demonstrate, for the first time, that the parasite may modify the IL-6-induced response through the modulation of its cysteine protease activity, suggesting that specific inhibitors may help to improve the immune cell activation and cardioprotective effects.
authors.affiliation: Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Nicolás Eric
authors.initials: NE
authors.lastname: Ponce
authors.forename: Eugenio Antonio
authors.initials: EA
authors.lastname: Carrera-Silva
authors.forename: Andrea Vanina
authors.initials: AV
authors.lastname: Pellegrini
authors.forename: Silvia Inés
authors.initials: SI
authors.lastname: Cazorla
authors.forename: Emilio Luis
authors.initials: EL
authors.lastname: Malchiodi
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Lima
authors.forename: Susana
authors.initials: S
authors.lastname: Gea
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D014355:Chagas Disease / Q000469:parasitology; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000494:pharmacology*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D006790:Host-Parasite Interactions; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015800:Protozoan Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000378:metabolism / Q000502:physiology
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D015800:Protozoan Proteins; D050796:STAT3 Transcription Factor; D051195:Toll-Like Receptor 2; C435145:chagasin, Trypanosoma; D050822:Cytokine Receptor gp130; D003546:Cysteine Endopeptidases; C063214:cruzipain