Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses
TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to...
| Autores: | , , , , , , , , , |
|---|---|
| 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:10486/677996 |
| Acceso en línea: | http://hdl.handle.net/10486/677996 https://dx.doi.org/10.1073/pnas.1506113113 |
| Access Level: | acceso abierto |
| Palabra clave: | Fibrosis SMADs TGF-β Thyroid hormone receptors Medicina |
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Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responsesAlonso-Merino, ElviraOrozco, Rosa MartínRuíz-Llorente, LidiaMartínez-Iglesias, Olaia A.Velasco-Martín, Juan PedroMontero-Pedrazuela, AnaFanjul-Rodríguez, LuisaContreras-Jurado, ConstanzaRegadera González, Javier Fco.Aranda, AnaFibrosisSMADsTGF-βThyroid hormone receptorsMedicinaTGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fundsNational Academy of SciencesDepartamento de Anatomía, Histología y NeurocienciaFacultad de MedicinaInstituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)20162016-06-14research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/677996https://dx.doi.org/10.1073/pnas.1506113113reponame: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:10486/6779962026-06-23T12:46:27Z |
| dc.title.none.fl_str_mv |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| title |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| spellingShingle |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses Alonso-Merino, Elvira Fibrosis SMADs TGF-β Thyroid hormone receptors Medicina |
| title_short |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| title_full |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| title_fullStr |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| title_full_unstemmed |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| title_sort |
Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses |
| dc.creator.none.fl_str_mv |
Alonso-Merino, Elvira Orozco, Rosa Martín Ruíz-Llorente, Lidia Martínez-Iglesias, Olaia A. Velasco-Martín, Juan Pedro Montero-Pedrazuela, Ana Fanjul-Rodríguez, Luisa Contreras-Jurado, Constanza Regadera González, Javier Fco. Aranda, Ana |
| author |
Alonso-Merino, Elvira |
| author_facet |
Alonso-Merino, Elvira Orozco, Rosa Martín Ruíz-Llorente, Lidia Martínez-Iglesias, Olaia A. Velasco-Martín, Juan Pedro Montero-Pedrazuela, Ana Fanjul-Rodríguez, Luisa Contreras-Jurado, Constanza Regadera González, Javier Fco. Aranda, Ana |
| author_role |
author |
| author2 |
Orozco, Rosa Martín Ruíz-Llorente, Lidia Martínez-Iglesias, Olaia A. Velasco-Martín, Juan Pedro Montero-Pedrazuela, Ana Fanjul-Rodríguez, Luisa Contreras-Jurado, Constanza Regadera González, Javier Fco. Aranda, Ana |
| author2_role |
author author author 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 |
Fibrosis SMADs TGF-β Thyroid hormone receptors Medicina |
| topic |
Fibrosis SMADs TGF-β Thyroid hormone receptors Medicina |
| description |
TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-06-14 |
| 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/10486/677996 https://dx.doi.org/10.1073/pnas.1506113113 |
| url |
http://hdl.handle.net/10486/677996 https://dx.doi.org/10.1073/pnas.1506113113 |
| 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 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
National Academy of Sciences |
| publisher.none.fl_str_mv |
National Academy of Sciences |
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reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
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Universidad Autónoma de Madrid |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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15.300719 |