The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia

Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-ΰ B and ERK, which play a key role in the response to...

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Autores: Contreras-Jurado, Constanza, Alonso-Merino, Elvira, Saiz-Ladera, Cristina, Valiño, Arturo José, Regadera, Javier, Alemany, Susana, Aranda, Ana
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/678055
Acceso en línea:http://hdl.handle.net/10486/678055
https://dx.doi.org/10.1038/srep30990
Access Level:acceso abierto
Palabra clave:Hormone
Thyroid hormone receptors
Hepatic inflammatory mediators
Interleukin 6
IL-6 signalling
Hormone signaling
Medicina
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spelling The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemiaContreras-Jurado, ConstanzaAlonso-Merino, ElviraSaiz-Ladera, CristinaValiño, Arturo JoséRegadera, JavierAlemany, SusanaAranda, AnaHormoneThyroid hormone receptorsHepatic inflammatory mediatorsInterleukin 6IL-6 signallingHormone signalingMedicinaDecreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-ΰ B and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.This work was supported by Grants: BFU2011-28058, BFU2014-53610P and SAF2015-71878-REDT from Ministerio de Economía y Competitividad; S2011/BMD-2328 from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos IIINature Publishing GroupDepartamento de Anatomía, Histología y NeurocienciaFacultad de MedicinaInstituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)20162016-08-03research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/678055https://dx.doi.org/10.1038/srep30990reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6780552026-06-23T12:46:27Z
dc.title.none.fl_str_mv The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
title The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
spellingShingle The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
Contreras-Jurado, Constanza
Hormone
Thyroid hormone receptors
Hepatic inflammatory mediators
Interleukin 6
IL-6 signalling
Hormone signaling
Medicina
title_short The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
title_full The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
title_fullStr The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
title_full_unstemmed The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
title_sort The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
dc.creator.none.fl_str_mv Contreras-Jurado, Constanza
Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
author Contreras-Jurado, Constanza
author_facet Contreras-Jurado, Constanza
Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
author_role author
author2 Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Anatomía, Histología y Neurociencia
Facultad de Medicina
Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)
dc.subject.none.fl_str_mv Hormone
Thyroid hormone receptors
Hepatic inflammatory mediators
Interleukin 6
IL-6 signalling
Hormone signaling
Medicina
topic Hormone
Thyroid hormone receptors
Hepatic inflammatory mediators
Interleukin 6
IL-6 signalling
Hormone signaling
Medicina
description Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-ΰ B and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-08-03
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/678055
https://dx.doi.org/10.1038/srep30990
url http://hdl.handle.net/10486/678055
https://dx.doi.org/10.1038/srep30990
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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