Artículo

La versión final de este artículo es de uso interno de la institución.
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including activating protein (AP)-1, NF-κB, 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 GRdependent 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. © FASEB.

Registro:

Documento: Artículo
Título:The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction
Autor:Liberman, A.C.; Refojo, D.; Druker, J.; Toscano, M.; Rein, T.; Holsboer, F.; Arzt, E.
Filiación:Laboratorio de Fisiología Y Biología Molecular, Departamento de Fisiología Y Biología Molecular Y Celular, Universidad de Buenos Aires and IFIBYNE-CONICET, Buenos Aires, Argentina
Max Planck Institute of Psychiatry, 80804 Munich, Germany
Division of Immunogenetics, Hospital de Clínicas Jose de San Martin, University of Buenos Aires, Avenida Cordoba, City of Buenos Aires, Argentina
Laboratorio de Fisiología Y Biología Molecular, FCEN, Ciudad Universitaria, 1428 Buenos Aires, Argentina
Palabras clave:Immunosupression; T helper inhibition; Transrepression; concanavalin A; gamma interferon; glucocorticoid receptor; transcription factor T bet; animal cell; animal tissue; article; binding site; controlled study; DNA binding; genetic transfection; in vitro study; in vivo study; mouse; nonhuman; priority journal; promoter region; protein expression; protein protein interaction; spleen cell; zinc finger motif; Animals; Cell Line; Glucocorticoids; Inflammation; Interferon Type II; Mice; Mice, Inbred BALB C; Mutation; Promoter Regions (Genetics); Protein Binding; Protein Interaction Mapping; Receptors, Glucocorticoid; Spleen; T-Box Domain Proteins; Transcription, Genetic; Transfection
Año:2007
Volumen:21
Número:4
Página de inicio:1177
Página de fin:1188
DOI: http://dx.doi.org/10.1096/fj.06-7452com
Título revista:FASEB Journal
Título revista abreviado:FASEB J.
ISSN:08926638
CODEN:FAJOE
CAS:concanavalin A, 11028-71-0; gamma interferon, 82115-62-6; Glucocorticoids; Interferon Type II, 82115-62-6; Receptors, Glucocorticoid; T-Box Domain Proteins; T-box transcription factor TBX21
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08926638_v21_n4_p1177_Liberman

Referencias:

  • Chrousos, G.P., The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation (1995) N. Engl. J. Med, 332, pp. 1351-1362
  • Cippitelli, M., Sica, A., Viggiano, V., Ye, J., Ghosh, P., Birrer, M.J., Young, H.A., Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun (1995) J. Biol. Chem, 270, pp. 12548-12556
  • Ashwell, J.D., Lu, F.W., Vacchio, M.S., Glucocorticoids in T cell development and function (2000) Annu. Rev. Immunol, 18, pp. 309-345
  • Cupps, T.R., Fauci, A.S., Corticosteroid-mediated immunoregulation in man (1982) Immunol. Rev, 65, pp. 133-155
  • Kovalovsky, D., Paez Pereda, M., Sauer, J., Perez Castro, C., Nahmod, V.E., Stalla, G.K., Holsboer, F., Arzt, E., The Th1 and Th2 cytokines IFN-gamma and IL-4 antagonize the inhibition of monocyte IL-1 receptor antagonist by glucocorticoids: Involvement of IL-1 (1998) Eur. J. Immunol, 28, pp. 2075-2085
  • Galon, J., Franchimont, D., Hiroi, N., Frey, G., Boettner, A., Ehrhart-Bornstein, M., O'Shea, J.J., Bornstein, S.R., Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells (2002) FASEB J, 16, pp. 61-71
  • Laue, L., Kawai, S., Brandon, D.D., Brightwell, D., Barnes, K., Knazek, R.A., Loriaux, D.L., Chrousos, G.P., Receptor-mediated effects of glucocorticoids on inflammation: Enhancement of the inflammatory response with a glucocorticoid antagonist (1988) J. Steroid. Biochem, 29, pp. 591-598
  • Boumpas, D.T., Chrousos, G.P., Wilder, R.L., Cupps, T.R., Balow, J.E., Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates (1993) Ann. Intern. Med, 119, pp. 1198-1208
  • Giguere, V., Hollenberg, S.M., Rosenfeld, M.G., Evans, R.M., Functional domains of the human glucocorticoid receptor (1986) Cell, 46, pp. 645-652
  • Nissen, R.M., Yamamoto, K.R., The glucocorticoid receptor inhibits NF-kappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain (2000) Genes Dev, 14, pp. 2314-2329
  • Jonat, C., Rahmsdorf, H.J., Park, K.K., Cato, A.C., Gebel, S., Ponta, H., Herrlich, P., Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone (1990) Cell, 62, pp. 1189-1204
  • Yang-Yen, H.F., Chambard, J.C., Sun, Y.L., Smeal, T., Schmidt, T.J., Drouin, J., Karin, M., Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction (1990) Cell, 62, pp. 1205-1215
  • Schule, R., Rangarajan, P., Kliewer, S., Ransone, L.J., Bolado, J., Yang, N., Verma, I.M., Evans, R.M., Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor (1990) Cell, 62, pp. 1217-1226
  • Caldenhoven, E., Liden, J., Wissink, S., Van de Stolpe, A., Raaijmakers, J., Koenderman, L., Okret, S., Van der Saag, P.T., Negative cross-talk between RelA and the glucocorticoid receptor: A possible mechanism for the antiinflammatory action of glucocorticoids (1995) Mol. Endocrinol, 9, pp. 401-412
  • Biola, A., Andreau, K., David, M., Sturm, M., Haake, M., Bertoglio, J., Pallardy, M., The glucocorticoid receptor and STAT6 physically and functionally interact in T-lymphocytes (2000) FEBS Lett, 487, pp. 229-233
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G., Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: Negative interference of activated glucocorticoid receptor with transcription factors (2000) J. Neuroimmunol, 109, pp. 16-22
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G., The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: Molecular mechanisms for gene repression (2003) Endocr. Rev, 24, pp. 488-522
  • Gottlicher, M., Heck, S., Herrlich, P., Transcriptional cross-talk, the second mode of steroid hormone receptor action (1998) J. Mol. Med, 76, pp. 480-489
  • Reichardt, H.M., Tuckermann, J.P., Gottlicher, M., Vujic, M., Weih, F., Angel, P., Herrlich, P., Schutz, G., Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor (2001) EMBO J, 20, pp. 7168-7173
  • Scheinman, R.I., Gualberto, A., Jewell, C.M., Cidlowski, J.A., Baldwin Jr., A.S., Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors (1995) Mol. Cell. Biol, 15, pp. 943-953
  • Adcock, I.M., Glucocorticoid-regulated transcription factors (2001) Pulm. Pharmacol. Ther, 14, pp. 211-219
  • Helmberg, A., Auphan, N., Caelles, C., Karin, M., Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor (1995) EMBO J, 14, pp. 452-460
  • Liden, J., Delaunay, F., Rafter, I., Gustafsson, J., Okret, S., A new function for the C-terminal zinc finger of the glucocorticoid receptor. Repression of RelA transactivation (1997) J. Biol. Chem, 272, pp. 21467-21472
  • Heck, S., Kullmann, M., Gast, A., Ponta, H., Rahmsdorf, H.J., Herrlich, P., Cato, A.C., A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1 (1994) EMBO J, 13, pp. 4087-4095
  • Tao, Y., Williams-Skipp, C., Scheinman, R.I., Mapping of glucocorticoid receptor DNA binding domain surfaces contributing to transrepression of NF-kappa B and induction of apoptosis (2001) J. Biol. Chem, 276, pp. 2329-2332
  • Szabo, S.J., Kim, S.T., Costa, G.L., Zhang, X., Fathman, C.G., Glimcher, L.H., A novel transcription factor, T-bet, directs Th1 lineage commitment (2000) Cell, 100, pp. 655-669
  • Szabo, S.J., Sullivan, B.M., Stemmann, C., Satoskar, A.R., Sleckman, B.P., Glimcher, L.H., Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells (2002) Science, 295, pp. 338-342
  • Robinson, D.S., O'Garra, A., Further checkpoints in Th1 development (2002) Immunity, 16, pp. 755-758
  • Young, H.A., Hardy, K.J., Interferon-gamma: Producer cells, activation stimuli, and molecular genetic regulation (1990) Pharmacol. Ther, 45, pp. 137-151
  • Abbas, A.K., Murphy, K.M., Sher, A., Functional diversity of helper T lymphocytes (1996) Nature, 383, pp. 787-793
  • Mosmann, T.R., Coffman, R.L., TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties (1989) Annu. Rev. Immunol, 7, pp. 145-173
  • Lighvani, A.A., Frucht, D.M., Jankovic, D., Yamane, H., Aliberti, J., Hissong, B.D., Nguyen, B.V., Paul, W.E., T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells (2001) Proc. Natl. Acad. Sci. U. S. A, 98, pp. 15137-15142
  • Mullen, A.C., High, F.A., Hutchins, A.S., Lee, H.W., Villarino, A.V., Livingston, D.M., Kung, A.L., Yang, S.Y., Role of T-bet in commitment of TH1 cells before IL-12-dependent selection (2001) Science, 292, pp. 1907-1910
  • Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T.L., Murphy, K.M., T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells (2002) Nat. Immunol, 3, pp. 549-557
  • Neurath, M.F., Weigmann, B., Finotto, S., Glickman, J., Nieuwenhuis, E., Iijima, H., Mizoguchi, A., Galle, P.R., The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease (2002) J. Exp. Med, 195, pp. 1129-1143
  • Blotta, M.H., DeKruyff, R.H., Umetsu, D.T., Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes (1997) J. Immunol, 158, pp. 5589-5595
  • Brinkmann, V., Kristofic, C., Regulation by corticosteroids of Th1 and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO- and CD45RO+ subsets (1995) J. Immunol, 155, pp. 3322-3328
  • Visser, J., van Boxel-Dezaire, A., Methorst, D., Brunt, T., de Kloet, E.R., Nagelkerken, L., Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro (1998) Blood, 91, pp. 4255-4264
  • Hu, X., Li, W.P., Meng, C., Ivashkiv, L.B., Inhibition of IFN-gamma signaling by glucocorticoids (2003) J. Immunol, 170, pp. 4833-4839
  • Franchimont, D., Galon, J., Gadina, M., Visconti, R., Zhou, Y., Aringer, M., Frucht, D.M., O'Shea, J.J., Inhibition of Th1 immune response by glucocorticoids: Dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes (2000) J. Immunol, 164, pp. 1768-1774
  • Miyaura, H., Iwata, M., Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids (2002) J. Immunol, 168, pp. 1087-1094
  • Boumpas, D.T., Paliogianni, F., Anastassiou, E.D., Balow, J.E., Glucocorticosteroid action on the immune system: Molecular and cellular aspects (1991) Clin. Exp. Rheumatol, 9, pp. 413-423
  • Braun, C.M., Huang, S.K., Bashian, G.G., Kagey-Sobotka, A., Lichtenstein, L.M., Essayan, D.M., Corticosteroid modulation of human, antigen-specific Th1 and Th2 responses (1997) J. Allergy Clin. Immunol, 100, pp. 400-407
  • Raiden, S., Polack, E., Nahmod, V., Labeur, M., Holsboer, F., Arzt, E., TRH receptor on immune cells: In vitro and in vivo stimulation of human lymphocyte and rat splenocyte DNA synthesis by TRH (1995) J. Clin. Immunol, 15, pp. 242-249
  • Siegel, M.D., Zhang, D.H., Ray, P., Ray, A., Activation of the interleukin-5 promoter by cAMP in murine EL-4 cells requires the GATA-3 and CLE0 elements (1995) J. Biol. Chem, 270, pp. 24548-24555
  • Hwang, E.S., Choi, A., Ho, I.C., Transcriptional regulation of GATA-3 by an intronic regulatory region and fetal liver zinc finger protein 1 (2002) J. Immunol, 169, pp. 248-253
  • Ouyang, W., Ranganath, S.H., Weindel, K., Bhattacharya, D., Murphy, T.L., Sha, W.C., Murphy, K.M., Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism (1998) Immunity, 9, pp. 745-755
  • Klein-Hessling, S., Jha, M.K., Santner-Nanan, B., Berberich-Siebelt, F., Baumruker, T., Schimpl, A., Serfling, E., Protein kinase A regulates GATA-3-dependent activation of IL-5 gene expression in Th2 cells (2003) J. Immunol, 170, pp. 2956-2961
  • Lee, H.J., Takemoto, N., Kurata, H., Kamogawa, Y., Miyatake, S., O'Garra, A., Arai, N., GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells (2000) J. Exp. Med, 192, pp. 105-115
  • Lee, H.J., Masuda, E.S., Arai, N., Arai, K., Yokota, T., Definition of cis-regulatory elements of the mouse interleukin-5 gene promoter. Involvement of nuclear factor of activated T cell-related factors in interleukin-5 expression (1995) J. Biol. Chem, 270, pp. 17541-17550
  • Fox, H.S., Bond, B.L., Parslow, T.G., Estrogen regulates the IFN-gamma promoter (1991) J. Immunol, 146, pp. 4362-4367
  • Rupprecht, R., Arriza, J.L., Spengler, D., Reul, J.M., Evans, R.M., Holsboer, F., Damm, K., Transactivation and synergistic properties of the mineralocorticoid receptor: Relationship to the glucocorticoid receptor (1993) Mol. Endocrinol, 7, pp. 597-603
  • McKean, D.J., Bell, M., Huntoon, C., Rastogi, S., Van Norstrand, M., Podzorski, R., Nilson, A., Paya, C., IL-1 receptor and TCR signals synergize to activate NF-kappa B-mediated gene transcription (1995) Int. Immunol, 7, pp. 9-20
  • Hollenberg, S.M., Evans, R.M., Multiple and cooperative trans-activation domains of the human glucocorticoid receptor (1988) Cell, 55, pp. 899-906
  • Paez-Pereda, M., Giacomini, D., Refojo, D., Nagashima, A.C., Hopfner, U., Grubler, Y., Chervin, A., Hentges, S.T., Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk (2003) Proc. Natl. Acad. Sci. U. S. A, 100, pp. 1034-1039
  • Costas, M., Trapp, T., Pereda, M.P., Sauer, J., Rupprecht, R., Nahmod, V.E., Reul, J.M., Arzt, E., Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis (1996) J. Clin. Invest, 98, pp. 1409-1416
  • Sakai, D.D., Helms, S., Carlstedt-Duke, J., Gustafsson, J.A., Rottman, F.M., Yamamoto, K.R., Hormone-mediated repression: A negative glucocorticoid response element from the bovine prolactin gene (1988) Genes Dev, 2, pp. 1144-1154
  • Novac, N., Baus, D., Dostert, A., Heinzel, T., Competition between glucocorticoid receptor and NF-kappaB for control of the human FasL promoter (2006) FASEB J, 20, pp. 1074-1081
  • Yudt, M.R., Jewell, C.M., Bienstock, R.J., Cidlowski, J.A., Molecular origins for the dominant negative function of human glucocorticoid receptor beta (2003) Mol. Cell. Biol, 23, pp. 4319-4330
  • Yin, Z., Chen, C., Szabo, S.J., Glimcher, L.H., Ray, A., Craft, J., T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-gamma by gammadelta T cells (2002) J. Immunol, 168, pp. 1566-1571
  • Cho, J.Y., Grigura, V., Murphy, T.L., Murphy, K., Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-gamma promoter (2003) Int. Immunol, 15, pp. 1149-1160
  • Hwang, E.S., Szabo, S.J., Schwartzberg, P.L., Glimcher, L.H., T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3 (2005) Science, 307, pp. 430-433
  • Hwang, E.S., Hong, J.H., Glimcher, L.H., IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508 (2005) J. Exp. Med, 202, pp. 1289-1300
  • Traenckner, E.B., Pahl, H.L., Henkel, T., Schmidt, K.N., Wilk, S., Baeuerle, P.A., Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli (1995) EMBO J, 14, pp. 2876-2883
  • Auphan, N., DiDonato, J.A., Rosette, C., Helmberg, A., Karin, M., Immunosuppression by glucocorticoids: Inhibition of NF-kappa B activity through induction of I kappa B synthesis (1995) Science, 270, pp. 286-290
  • O'Shea, J.J., Park, H., Pesu, M., Borie, D., Changelian, P., New strategies for immunosuppression: Interfering with cytokines by targeting the Jak/Stat pathway (2005) Curr. Opin. Rheumatol, 17, pp. 305-311

Citas:

---------- APA ----------
Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F. & Arzt, E. (2007) . The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB Journal, 21(4), 1177-1188.
http://dx.doi.org/10.1096/fj.06-7452com
---------- CHICAGO ----------
Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F., et al. "The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction" . FASEB Journal 21, no. 4 (2007) : 1177-1188.
http://dx.doi.org/10.1096/fj.06-7452com
---------- MLA ----------
Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F., et al. "The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction" . FASEB Journal, vol. 21, no. 4, 2007, pp. 1177-1188.
http://dx.doi.org/10.1096/fj.06-7452com
---------- VANCOUVER ----------
Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., Holsboer, F., et al. The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J. 2007;21(4):1177-1188.
http://dx.doi.org/10.1096/fj.06-7452com