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

• Autores: 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.
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: PLoS ONE 2012;7(4)
• Materia: 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
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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.