Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells

Autores
Ponce, Nicolás Eric; Carrera Silva, Eugenio Antonio; Pellegrini, Andrea Vanina; Cazorla, Silvia Ines; Malchiodi, Emilio Luis; Lima, Ana Paula; Gea, Susana; Aoki, Maria del Pilar
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells. Ponce NE, Carrera-Silva EA, Pellegrini AV, Cazorla SI, Malchiodi EL, Lima AP, Gea S, Aoki MP. Biochim Biophys Acta - Mol Basis Dis, in press. IF = 5.39. 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.
Fil: Ponce, Nicolás Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Pellegrini, Andrea Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Cazorla, Silvia Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentina
Fil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentina
Fil: Lima, Ana Paula. Universidade Federal do Rio de Janeiro; Brasil
Fil: Gea, Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Aoki, Maria del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Materia
Trypanosoma Cruzi
Chagas Disease
Il6
Gp130
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/8065
Acceder
id CONICETDig_7e9c547628a45437ebc9c35a4c4998d0
oai_identifier_str oai:ri.conicet.gov.ar:11336/8065
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cellsPonce, Nicolás EricCarrera Silva, Eugenio AntonioPellegrini, Andrea VaninaCazorla, Silvia InesMalchiodi, Emilio LuisLima, Ana PaulaGea, SusanaAoki, Maria del PilarTrypanosoma CruziChagas DiseaseIl6Gp130https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells. Ponce NE, Carrera-Silva EA, Pellegrini AV, Cazorla SI, Malchiodi EL, Lima AP, Gea S, Aoki MP. Biochim Biophys Acta - Mol Basis Dis, in press. IF = 5.39. 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.Fil: Ponce, Nicolás Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Pellegrini, Andrea Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Cazorla, Silvia Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Lima, Ana Paula. Universidade Federal do Rio de Janeiro; BrasilFil: Gea, Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaFil: Aoki, Maria del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; ArgentinaElsevier Science2013-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8065Ponce, Nicolás Eric; Carrera Silva, Eugenio Antonio; Pellegrini, Andrea Vanina; Cazorla, Silvia Ines; Malchiodi, Emilio Luis; et al.; Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells; Elsevier Science; Biochimica Et Biophysica Acta - Molecular Basis Of Disease; 1832; 3; 3-2013; 485-4940925-4439enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0925443912002888info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbadis.2012.12.003info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:48:47Zoai:ri.conicet.gov.ar:11336/8065instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:48:47.927CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
title Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
spellingShingle Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
Ponce, Nicolás Eric
Trypanosoma Cruzi
Chagas Disease
Il6
Gp130
title_short Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
title_full Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
title_fullStr Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
title_full_unstemmed Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
title_sort Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
dc.creator.none.fl_str_mv Ponce, Nicolás Eric
Carrera Silva, Eugenio Antonio
Pellegrini, Andrea Vanina
Cazorla, Silvia Ines
Malchiodi, Emilio Luis
Lima, Ana Paula
Gea, Susana
Aoki, Maria del Pilar
author Ponce, Nicolás Eric
author_facet Ponce, Nicolás Eric
Carrera Silva, Eugenio Antonio
Pellegrini, Andrea Vanina
Cazorla, Silvia Ines
Malchiodi, Emilio Luis
Lima, Ana Paula
Gea, Susana
Aoki, Maria del Pilar
author_role author
author2 Carrera Silva, Eugenio Antonio
Pellegrini, Andrea Vanina
Cazorla, Silvia Ines
Malchiodi, Emilio Luis
Lima, Ana Paula
Gea, Susana
Aoki, Maria del Pilar
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trypanosoma Cruzi
Chagas Disease
Il6
Gp130
topic Trypanosoma Cruzi
Chagas Disease
Il6
Gp130
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells. Ponce NE, Carrera-Silva EA, Pellegrini AV, Cazorla SI, Malchiodi EL, Lima AP, Gea S, Aoki MP. Biochim Biophys Acta - Mol Basis Dis, in press. IF = 5.39. 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.
Fil: Ponce, Nicolás Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Pellegrini, Andrea Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Cazorla, Silvia Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentina
Fil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentina
Fil: Lima, Ana Paula. Universidade Federal do Rio de Janeiro; Brasil
Fil: Gea, Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
Fil: Aoki, Maria del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Bioquímica Clínica E Inmunología; Argentina
description Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells. Ponce NE, Carrera-Silva EA, Pellegrini AV, Cazorla SI, Malchiodi EL, Lima AP, Gea S, Aoki MP. Biochim Biophys Acta - Mol Basis Dis, in press. IF = 5.39. 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.
publishDate 2013
dc.date.none.fl_str_mv 2013-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/8065
Ponce, Nicolás Eric; Carrera Silva, Eugenio Antonio; Pellegrini, Andrea Vanina; Cazorla, Silvia Ines; Malchiodi, Emilio Luis; et al.; Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells; Elsevier Science; Biochimica Et Biophysica Acta - Molecular Basis Of Disease; 1832; 3; 3-2013; 485-494
0925-4439
url http://hdl.handle.net/11336/8065
identifier_str_mv Ponce, Nicolás Eric; Carrera Silva, Eugenio Antonio; Pellegrini, Andrea Vanina; Cazorla, Silvia Ines; Malchiodi, Emilio Luis; et al.; Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukine-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells; Elsevier Science; Biochimica Et Biophysica Acta - Molecular Basis Of Disease; 1832; 3; 3-2013; 485-494
0925-4439
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0925443912002888
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbadis.2012.12.003
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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