Artículos de revistas
The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
Fecha
2007-04Registro en:
Liberman, Ana Clara; Refojo, Damian; Druker, Jimena; Toscano, Marta Alicia; Rein, Theo; et al.; The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction; Federation of American Societies for Experimental Biology; FASEB Journal; 21; 4; 4-2007; 1177-1188
0892-6638
1530-6860
CONICET Digital
CONICET
Autor
Liberman, Ana Clara
Refojo, Damian
Druker, Jimena
Toscano, Marta Alicia
Rein, Theo
Holsboer, Florian
Arzt, Eduardo Simon
Resumen
Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including AP-1, NFkB and NFAT. GCs inhibit Th1 cytokines and promote a shift towards Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on interferon-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.