Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

ANA C LIBERMAN *; MARÍA ANTUNICA NOGUEROL *; VIVIANE FERRAZ-DE-PAULA; JOAO PALERMO-NETO; CARLA N CASTRO; JIMENA DRUKER; FLORIAN HOLSBOER; MARCELO J PERONE; SARAH GERLO; KAROLIEN DE BOSSCHER; GUY HAEGEMAN; EDUARDO ARZT

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 10

1932-6203

Compound A (CpdA) is a dissociating non-steroidal glucocorticoidreceptor (GR) ligand which has anti-inflammatory properties exerted by downmodulatingproinflammatory gene expression. By favouring GR monomer formation,CpdA does not enhance glucocorticoid (GC) response element-driven geneexpression, resulting in a reduced side effect profile as compared to GCs. Consideringthe importance of Th1/Th2 balance in the final outcome of immune and inflammatoryresponses, we analyzed how selective GR modulation differentially regulates theactivity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation,respectively. RESULTS: Using Western analysis and reporter gene assays, we show inmurine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressivemechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPKinductionof GATA-3 phosphorylation and nuclear translocation. CpdA effects arereversed by the GR antagonist RU38486, proving the involvement of GR in theseactions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts oncytokine production shown by a decrease in IFN-γ and an increase in IL-5 production,respectively. CONCLUSIONS: Taken together, through their effect favoring Th2 overTh1 responses, particular dissociated GR ligands, for which CpdA represents aparadigm, hold potential for the application in Th1-mediated immune disorders.