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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-κB and ERK, which play a key role in the response to in...

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Autores principales: Contreras-Jurado, Constanza, Alonso-Merino, Elvira, Saiz-Ladera, Cristina, Valiño, Arturo José, Regadera, Javier, Alemany, Susana, Aranda, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971531/
https://www.ncbi.nlm.nih.gov/pubmed/27484112
http://dx.doi.org/10.1038/srep30990
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author Contreras-Jurado, Constanza
Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
author_facet Contreras-Jurado, Constanza
Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
author_sort Contreras-Jurado, Constanza
collection PubMed
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-κB 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.
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spelling pubmed-49715312016-08-11 The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia Contreras-Jurado, Constanza Alonso-Merino, Elvira Saiz-Ladera, Cristina Valiño, Arturo José Regadera, Javier Alemany, Susana Aranda, Ana Sci Rep Article 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-κB 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. Nature Publishing Group 2016-08-03 /pmc/articles/PMC4971531/ /pubmed/27484112 http://dx.doi.org/10.1038/srep30990 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Contreras-Jurado, Constanza
Alonso-Merino, Elvira
Saiz-Ladera, Cristina
Valiño, Arturo José
Regadera, Javier
Alemany, Susana
Aranda, Ana
The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia
title 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_short The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia
title_sort thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971531/
https://www.ncbi.nlm.nih.gov/pubmed/27484112
http://dx.doi.org/10.1038/srep30990
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