Compound A (CpdA), a selective glucocorticoid receptor (GR) modifier, is capable of diferentially regulate GATA-3 (Th2) and T-bet (Th1) transcription factors (TFs)

ANTUNICA NOGUEROL, M.; LIBERMAN, A.C.; CASTRO, C.N.; PERONE, M.J.; DE BOSSCHER, K.; HAEGEMAN, G.; ARZT, E.

Buenos Aires

Congreso; III Iberoamerican Congress on NeuroImmunoModulation; 2009

Recently, Compound A (CpdA), was found to be a selective GR modifier. The potential therapeutic advantage of CpdA over GCs is that it does not stimulate glucocorticoid response element-driven gene expression, accepted as the basis for undesirable side effects. CpdA regulates GR interfering with the activity of TFs that drive cytokine gene expression. We investigated  the effects of CpdA in the differentiation processes of Th1 and Th2 cells, its modulation of the transcriptional activity of T-bet (Th1) and GATA-3 (Th2) and how its effects differ from the classical GCs.We study the regulation of CpdA (10-6M) on T-bet and GATA-3. Transcriptional activity was studied using transfection assays on EL-4 cells using GATA-3 and T-bet response elements cloned upstream of the luciferase gene and also the IL-5 (Th2) and IFN-γ (Th1) promoters. CpdA inhibits T-bet transcriptional activity on T-bet response elements (38%, p<0.01) and also on IFN-γ promoter (30%, p<0.01). On the contrary, CpdA induces cAMP-mediated GATA-3 transcriptional activity on GATA-3 response elements (50%, p<0.01) and on IL-5 promoter (57%, p<0.01). The latter activation may be due to a further induction of phospho-p38 MAPK activity. Therefore, CpdA may induce a Th2 anti-inflammatory response.