title: Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells.
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.
authors.affiliation: Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Investigación Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Liberman
authors.forename: Maria
authors.initials: M
authors.lastname: Antunica-Noguerol
authors.forename: Viviane
authors.initials: V
authors.lastname: Ferraz-de-Paula
authors.forename: Joao
authors.initials: J
authors.lastname: Palermo-Neto
authors.forename: Carla N
authors.initials: CN
authors.lastname: Castro
authors.forename: Jimena
authors.initials: J
authors.lastname: Druker
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Perone
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000085:Acetates; D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors; D013154:Spleen / Q000187:drug effects* / Q000276:immunology; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014439:Tyramine / Q000031:analogs & derivatives; D000098815:T-bet Transcription Factor
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D001388:Aziridines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D000644:Quaternary Ammonium Compounds; D011965:Receptors, Glucocorticoid; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015735:Mifepristone; D007371:Interferon-gamma; D014439:Tyramine