IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
Glucocorticoids inhbit T-bet transcriptional activity by direct protein-protein interaction
Autor/es:
LIBERMAN, A, REFOJO, D, DRUKER, J, TOSCANO, M, REIN, T, HOLSBOER, F, ARZT,E.
Revista:
FASEB JOURNAL
Referencias:
Año: 2007 vol. 21 p. 1177 - 1188
ISSN:
0892-6638
Resumen:
Glucocorticoids (GCs) immunosuppression acts via regulation of several
transcription factors (TF), including activating protein (AP)-1,
NF-kappaB, and NFAT. GCs inhibit Th1 cytokines and promote a shift
toward 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 IFN-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.