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Abstract:

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.

Registro:

Documento: Artículo
Título:Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells
Autor: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.
Filiación:Laboratorio de Fisiología y Biología Molecular, Dep. de Fisiologia y Bio. Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Univ. de Buenos Aires and Inst. de Investigacion Bio. de Buenos Aires (IBioBA)-CONICET-Partner Inst, Buenos Aires, Argentina
Neuroimmunomodulation Research Group, FMVZ-USP, San Pablo, Brazil
Max Planck Institute of Psychiatry, Munich, Germany
Laboratory for Eukaryotic Gene Expression and Signal Transduction, Ghent University, Ghent, Belgium
VIB Department of Medical Protein Research, UGent, Ghent, Belgium
Palabras clave: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
Año:2012
Volumen:7
Número:4
DOI: http://dx.doi.org/10.1371/journal.pone.0035155
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CAS:dexamethasone, 50-02-2; gamma interferon, 82115-62-6; mifepristone, 84371-65-3; transcription factor GATA 3, 137878-55-8; 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride; Aziridines; GATA3 Transcription Factor; Gata3 protein, mouse; Interferon-gamma, 82115-62-6; Mifepristone, 84371-65-3; Quaternary Ammonium Compounds; Receptors, Glucocorticoid; T-Box Domain Proteins; T-box transcription factor TBX21
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_19326203_v7_n4_p_Liberman.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v7_n4_p_Liberman

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Citas:

---------- APA ----------
Liberman, A.C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C.N., Druker, J., Holsboer, F.,..., Arzt, E. (2012) . Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells. PLoS ONE, 7(4).
http://dx.doi.org/10.1371/journal.pone.0035155
---------- CHICAGO ----------
Liberman, A.C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C.N., Druker, J., et al. "Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells" . PLoS ONE 7, no. 4 (2012).
http://dx.doi.org/10.1371/journal.pone.0035155
---------- MLA ----------
Liberman, A.C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C.N., Druker, J., et al. "Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells" . PLoS ONE, vol. 7, no. 4, 2012.
http://dx.doi.org/10.1371/journal.pone.0035155
---------- VANCOUVER ----------
Liberman, A.C., Antunica-Noguerol, M., Ferraz-de-Paula, V., Palermo-Neto, J., Castro, C.N., Druker, J., et al. Compound a, a dissociated glucocorticoid receptor modulator, inhibits t-bet (th1) and induces gata-3 (th2) activity in immune cells. PLoS ONE. 2012;7(4).
http://dx.doi.org/10.1371/journal.pone.0035155