Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells

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Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven ge...

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Autores principales:	Liberman, A.C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C.N., Druker, J., Holsboer, F., Perone, M.J., Gerlo, S., de Bosscher, K., Haegeman, G., Arzt, E.
Formato:	Artículo publishedVersion
Publicado:	2012
Materias:	compound A dexamethasone gamma interferon glucocorticoid receptor interleukin 5 mifepristone transcription factor GATA 3 unclassified drug 2 (4 acetoxyphenyl) 2 chloro N methyl ethylammonium chloride 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride aziridine derivative Gata3 protein, mouse quaternary ammonium derivative T box transcription factor T box transcription factor TBX21 T-box transcription factor TBX21 animal cell article cell differentiation controlled study cytokine production dimerization enzyme linked immunosorbent assay gene expression immune response immunocompetent cell ligand binding mouse nonhuman protein expression protein phosphorylation reporter gene spleen cell Th1 cell Th2 cell animal Bagg albino mouse biosynthesis drug antagonism drug effect drug potentiation immunology spleen T lymphocyte Th1 Th2 balance Murinae Animals Aziridines GATA3 Transcription Factor Interferon-gamma Mice Mice, Inbred BALB C Mifepristone Quaternary Ammonium Compounds Receptors, Glucocorticoid Spleen T-Box Domain Proteins T-Lymphocytes Th1 Cells Th1-Th2 Balance Th2 Cells
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_19326203_v7_n4_p_Liberman https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_19326203_v7_n4_p_Liberman_oai
Aporte de:	Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires

id	I28-R145-paper_19326203_v7_n4_p_Liberman_oai
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spelling	I28-R145-paper_19326203_v7_n4_p_Liberman_oai2024-08-16 Liberman, A.C. Antunica-Noguerol, M. Ferraz-de-Paula, V. Palermo-Neto, J. Castro, C.N. Druker, J. Holsboer, F. Perone, M.J. Gerlo, S. de Bosscher, K. Haegeman, G. Arzt, E. 2012 Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. © 2012 Liberman et al. Fil:Liberman, A.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Castro, C.N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Druker, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. application/pdf http://hdl.handle.net/20.500.12110/paper_19326203_v7_n4_p_Liberman info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar PLoS ONE 2012;7(4) compound A dexamethasone gamma interferon glucocorticoid receptor interleukin 5 mifepristone transcription factor GATA 3 unclassified drug 2 (4 acetoxyphenyl) 2 chloro N methyl ethylammonium chloride 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride aziridine derivative gamma interferon Gata3 protein, mouse glucocorticoid receptor mifepristone quaternary ammonium derivative T box transcription factor T box transcription factor TBX21 T-box transcription factor TBX21 transcription factor GATA 3 animal cell article cell differentiation controlled study cytokine production dimerization enzyme linked immunosorbent assay gene expression immune response immunocompetent cell ligand binding mouse nonhuman protein expression protein phosphorylation reporter gene spleen cell Th1 cell Th2 cell animal Bagg albino mouse biosynthesis drug antagonism drug effect drug potentiation immunology spleen T lymphocyte Th1 Th2 balance Murinae Animals Aziridines GATA3 Transcription Factor Interferon-gamma Mice Mice, Inbred BALB C Mifepristone Quaternary Ammonium Compounds Receptors, Glucocorticoid Spleen T-Box Domain Proteins T-Lymphocytes Th1 Cells Th1-Th2 Balance Th2 Cells Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_19326203_v7_n4_p_Liberman_oai
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-145
collection	Repositorio Digital de la Universidad de Buenos Aires (UBA)
topic	compound A dexamethasone gamma interferon glucocorticoid receptor interleukin 5 mifepristone transcription factor GATA 3 unclassified drug 2 (4 acetoxyphenyl) 2 chloro N methyl ethylammonium chloride 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride aziridine derivative gamma interferon Gata3 protein, mouse glucocorticoid receptor mifepristone quaternary ammonium derivative T box transcription factor T box transcription factor TBX21 T-box transcription factor TBX21 transcription factor GATA 3 animal cell article cell differentiation controlled study cytokine production dimerization enzyme linked immunosorbent assay gene expression immune response immunocompetent cell ligand binding mouse nonhuman protein expression protein phosphorylation reporter gene spleen cell Th1 cell Th2 cell animal Bagg albino mouse biosynthesis drug antagonism drug effect drug potentiation immunology spleen T lymphocyte Th1 Th2 balance Murinae Animals Aziridines GATA3 Transcription Factor Interferon-gamma Mice Mice, Inbred BALB C Mifepristone Quaternary Ammonium Compounds Receptors, Glucocorticoid Spleen T-Box Domain Proteins T-Lymphocytes Th1 Cells Th1-Th2 Balance Th2 Cells
spellingShingle	compound A dexamethasone gamma interferon glucocorticoid receptor interleukin 5 mifepristone transcription factor GATA 3 unclassified drug 2 (4 acetoxyphenyl) 2 chloro N methyl ethylammonium chloride 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride aziridine derivative gamma interferon Gata3 protein, mouse glucocorticoid receptor mifepristone quaternary ammonium derivative T box transcription factor T box transcription factor TBX21 T-box transcription factor TBX21 transcription factor GATA 3 animal cell article cell differentiation controlled study cytokine production dimerization enzyme linked immunosorbent assay gene expression immune response immunocompetent cell ligand binding mouse nonhuman protein expression protein phosphorylation reporter gene spleen cell Th1 cell Th2 cell animal Bagg albino mouse biosynthesis drug antagonism drug effect drug potentiation immunology spleen T lymphocyte Th1 Th2 balance Murinae Animals Aziridines GATA3 Transcription Factor Interferon-gamma Mice Mice, Inbred BALB C Mifepristone Quaternary Ammonium Compounds Receptors, Glucocorticoid Spleen T-Box Domain Proteins T-Lymphocytes Th1 Cells Th1-Th2 Balance Th2 Cells Liberman, A.C. Antunica-Noguerol, M. Ferraz-de-Paula, V. Palermo-Neto, J. Castro, C.N. Druker, J. Holsboer, F. Perone, M.J. Gerlo, S. de Bosscher, K. Haegeman, G. Arzt, E. Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
topic_facet	compound A dexamethasone gamma interferon glucocorticoid receptor interleukin 5 mifepristone transcription factor GATA 3 unclassified drug 2 (4 acetoxyphenyl) 2 chloro N methyl ethylammonium chloride 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride aziridine derivative gamma interferon Gata3 protein, mouse glucocorticoid receptor mifepristone quaternary ammonium derivative T box transcription factor T box transcription factor TBX21 T-box transcription factor TBX21 transcription factor GATA 3 animal cell article cell differentiation controlled study cytokine production dimerization enzyme linked immunosorbent assay gene expression immune response immunocompetent cell ligand binding mouse nonhuman protein expression protein phosphorylation reporter gene spleen cell Th1 cell Th2 cell animal Bagg albino mouse biosynthesis drug antagonism drug effect drug potentiation immunology spleen T lymphocyte Th1 Th2 balance Murinae Animals Aziridines GATA3 Transcription Factor Interferon-gamma Mice Mice, Inbred BALB C Mifepristone Quaternary Ammonium Compounds Receptors, Glucocorticoid Spleen T-Box Domain Proteins T-Lymphocytes Th1 Cells Th1-Th2 Balance Th2 Cells
description	Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. © 2012 Liberman et al.
format	Artículo Artículo publishedVersion
author	Liberman, A.C. Antunica-Noguerol, M. Ferraz-de-Paula, V. Palermo-Neto, J. Castro, C.N. Druker, J. Holsboer, F. Perone, M.J. Gerlo, S. de Bosscher, K. Haegeman, G. Arzt, E.
author_facet	Liberman, A.C. Antunica-Noguerol, M. Ferraz-de-Paula, V. Palermo-Neto, J. Castro, C.N. Druker, J. Holsboer, F. Perone, M.J. Gerlo, S. de Bosscher, K. Haegeman, G. Arzt, E.
author_sort	Liberman, A.C.
title	Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
title_short	Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
title_full	Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
title_fullStr	Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
title_full_unstemmed	Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
title_sort	compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
publishDate	2012
url	http://hdl.handle.net/20.500.12110/paper_19326203_v7_n4_p_Liberman https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_19326203_v7_n4_p_Liberman_oai
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Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells

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