PERONE Marcelo Javier
Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells
LIBERMAN, AC; ANTUNICA NOGUEROL, M; FERRAZ DE PAULA, V; PALERMO-NETO, J; CASTRO, CN; DRUKER, J; HOLSBOER, F; PERONE, MJ; GERLO, S; DE BOSSCHER, K; HAEGEMAN, G; ARZT, E
PUBLIC LIBRARY SCIENCE
Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 1
Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has antiinflammatoryproperties exerted by down-modulating proinflammatory gene expression. By favouring GR monomerformation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reducedside effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune andinflammatory 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-betactivity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction ofGATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving theinvolvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokineproduction shown by a decrease in IFN-c and an increase in IL-5 production, respectively.Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, forwhich CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders.