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The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction

Ana C. Liberman^*, Damian Refojo^*, Jimena Druker^*, Marta Toscano, Theo Rein, Florian Holsboer and Eduardo Arzt^*,1

^* Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBYNE-CONICET, Buenos Aires, Argentina;

Max Planck Institute of Psychiatry, 80804 Munich, Germany; and

Division of Immunogenetics, Hospital de Clínicas Jose de San Martin, Faculty of Medicine, University of Buenos Aires, Avenida Cordoba, City of Buenos Aires, Argentina

¹Correspondence: Laboratorio de Fisiología y Biología Molecular, FCEN, Universidad de Buenos Aires, Ciudad Universitaria, 1428 Buenos Aires, Argentina. E-mail: earzt{at}fbmc.fcen.uba.ar

Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including activating protein (AP)-1, NF-B, 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.—Liberman, A. C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F., Arzt, E. The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction.

Key Words: transrepression • T helper inhibition • immunosupression

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