The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction

Autores
Liberman, Ana Clara; Refojo, Damian; Druker, Jimena; Toscano, Marta Alicia; Rein, Theo; Holsboer, Florian; Arzt, Eduardo Simon
Año de publicación
2007
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including AP-1, NFkB and NFAT. GCs inhibit Th1 cytokines and promote a shift towards Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on interferon-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.
Fil: Liberman, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Druker, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Toscano, Marta Alicia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Rein, Theo. Max Planck Institut für Psychiatrie; Alemania
Fil: Holsboer, Florian. Max Planck Institut für Psychiatrie; Alemania
Fil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Materia
Glucocorticoid
T-Bet
Th1
Inflammation
Immunosupression
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/27525
Acceder
id CONICETDig_13a6b2312aa7d8a186d98793d9d1ad29
oai_identifier_str oai:ri.conicet.gov.ar:11336/27525
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interactionLiberman, Ana ClaraRefojo, DamianDruker, JimenaToscano, Marta AliciaRein, TheoHolsboer, FlorianArzt, Eduardo SimonGlucocorticoidT-BetTh1InflammationImmunosupressionhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including AP-1, NFkB and NFAT. GCs inhibit Th1 cytokines and promote a shift towards Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on interferon-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.Fil: Liberman, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Druker, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Toscano, Marta Alicia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rein, Theo. Max Planck Institut für Psychiatrie; AlemaniaFil: Holsboer, Florian. Max Planck Institut für Psychiatrie; AlemaniaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFederation of American Societies for Experimental Biology2007-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/27525Liberman, Ana Clara; Refojo, Damian; Druker, Jimena; Toscano, Marta Alicia; Rein, Theo; et al.; The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction; Federation of American Societies for Experimental Biology; FASEB Journal; 21; 4; 4-2007; 1177-11880892-66381530-6860CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.fasebj.org/content/21/4/1177.abstract?sid=83c5226a-8236-4679-a292-92c045b5536einfo:eu-repo/semantics/altIdentifier/doi/10.1096/fj.06-7452cominfo:eu-repo/semantics/altIdentifier/pmid/17215482info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:15:59Zoai:ri.conicet.gov.ar:11336/27525instacron: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:34982025-10-15 15:15:59.989CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
title The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
spellingShingle The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
Liberman, Ana Clara
Glucocorticoid
T-Bet
Th1
Inflammation
Immunosupression
title_short The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
title_full The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
title_fullStr The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
title_full_unstemmed The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
title_sort The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
dc.creator.none.fl_str_mv Liberman, Ana Clara
Refojo, Damian
Druker, Jimena
Toscano, Marta Alicia
Rein, Theo
Holsboer, Florian
Arzt, Eduardo Simon
author Liberman, Ana Clara
author_facet Liberman, Ana Clara
Refojo, Damian
Druker, Jimena
Toscano, Marta Alicia
Rein, Theo
Holsboer, Florian
Arzt, Eduardo Simon
author_role author
author2 Refojo, Damian
Druker, Jimena
Toscano, Marta Alicia
Rein, Theo
Holsboer, Florian
Arzt, Eduardo Simon
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Glucocorticoid
T-Bet
Th1
Inflammation
Immunosupression
topic Glucocorticoid
T-Bet
Th1
Inflammation
Immunosupression
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including AP-1, NFkB and NFAT. GCs inhibit Th1 cytokines and promote a shift towards Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on interferon-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.
Fil: Liberman, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Druker, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Toscano, Marta Alicia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Rein, Theo. Max Planck Institut für Psychiatrie; Alemania
Fil: Holsboer, Florian. Max Planck Institut für Psychiatrie; Alemania
Fil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
description Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including AP-1, NFkB and NFAT. GCs inhibit Th1 cytokines and promote a shift towards Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on interferon-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.
publishDate 2007
dc.date.none.fl_str_mv 2007-04
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/11336/27525
Liberman, Ana Clara; Refojo, Damian; Druker, Jimena; Toscano, Marta Alicia; Rein, Theo; et al.; The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction; Federation of American Societies for Experimental Biology; FASEB Journal; 21; 4; 4-2007; 1177-1188
0892-6638
1530-6860
CONICET Digital
CONICET
url http://hdl.handle.net/11336/27525
identifier_str_mv Liberman, Ana Clara; Refojo, Damian; Druker, Jimena; Toscano, Marta Alicia; Rein, Theo; et al.; The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction; Federation of American Societies for Experimental Biology; FASEB Journal; 21; 4; 4-2007; 1177-1188
0892-6638
1530-6860
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.fasebj.org/content/21/4/1177.abstract?sid=83c5226a-8236-4679-a292-92c045b5536e
info:eu-repo/semantics/altIdentifier/doi/10.1096/fj.06-7452com
info:eu-repo/semantics/altIdentifier/pmid/17215482
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Federation of American Societies for Experimental Biology
publisher.none.fl_str_mv Federation of American Societies for Experimental Biology
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 13.22299

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