Glucocorticoids inhbit T-bet transcriptional activity by direct protein-protein interaction.

ANA C. LIBERMAN, DAMIAN REFOJO, JIMENA DRUKER, MATA TOSCANO, THEO REIN, FLORIAN HOLSBOER AND EDUARDO ARZT

FASEB JOURNAL

Año: 2006

0892-6638

Glucocorticoid (GC) immunosuppressive action involves the regulation of several transcription factors such as AP-1, NFkB, NFAT and STAT family members. Transcription factor T-bet is pivotal for the acquisition of Th1 phenotype. GCs regulate Th1 cytokines and favor a shift towards Th2 differentiation by selectevely inhibiting Th1 phenotype. We first show that GC inhibit T-bet ability to activate gene expression. Using transfected cell lines and endogenous GR and T-bet in primary cultures we describe that GR physically interacts with T-bet. This physical mutual repression also bloks GR transcriptional activity.  The mechansim of inhibition also involves reduction of T-bet binding to the DNA and T-bet interaction with endogenous DNA sequences. With specific mutations of the GR we show that the first N terminal zinc finger region of the GR is required for the transcriptional inhibition of T-bet activity. Moreover, dexamethasone treatment of T cell cultures causes a significant reduction of not only T-bet mRNA but also protein expression. Therefore, GCs are also able to inhibit T-bet activity by an additional mechanism involving transcriptional levels. We analyzed the functional consequences of GR/T-bet interaction in the regulation of INF-gamma promoter showing that GCs inhibit the transcriptional activity of T-bet on this promoter dose dependently.Given the role of T-bet in T cell differentiation and inflammation, we propose that GR interaction with T-bet system represents and important mechanism to understand the immunosuppressive properties of GCs.