Accessible Requires Authentication Published by De Gruyter April 23, 2015

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Sabine Hübner, Lien Dejager, Claude Libert and Jan P. Tuckermann
From the journal Biological Chemistry


Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.

Corresponding author: Jan P. Tuckermann, Institute for Comparative Molecular Endocrinology (CME), University of Ulm, Helmholtzstrasse 8/1, 89075 Ulm, Germany, e-mail:
aThese authors contributed equally to this work.


JT acknowledges support from Deutsche Forschungsgemeinschaft ‘Immunobone’ (SPP 1468 Tu220/6–2, Collaborative Research Centre 1149) from KaroBioScience Foundation and the EU FP7 Programme BRAINAGE.


Abraham, S.M., Lawrence, T., Kleiman, A., Warden, P., Medghalchi, M., Tuckermann, J., Saklatvala, J., and Clark, A.R. (2006). Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203, 1883–1889. Search in Google Scholar

Ayroldi, E. and Riccardi, C. (2009). Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 23, 3649–3658. Search in Google Scholar

Ayroldi, E., Migliorati, G., Bruscoli, S., Marchetti, C., Zollo, O., Cannarile, L., D’Adamio, F., and Riccardiand, C. (2001). Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 98, 743–753. Search in Google Scholar

Baschant, U., Frappart, L., Rauchhaus, U., Bruns, L., Reichardt, H.M., Kamradt, T., Brauer, R., and Tuckermann, J.P. (2011). Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proc. Natl. Acad. Sci. USA 108, 19317–19322. Search in Google Scholar

Baschant, U., Lane, N.E., and Tuckermann, J. (2012). The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat. Rev. Rheumatol. 8, 645–655. Search in Google Scholar

Bhattacharyya, S., Brown, D.E., Brewer, J.A., Vogt, S.K., and Muglia, L.J. (2007). Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109, 4313–4319. Search in Google Scholar

Bhattacharyya, S., Ratajczak, C.K., Vogt, S.K., Kelley, C., Colonna, M., Schreiber, R.D., and Muglia, L.J. (2010). TAK1 targeting by glucocorticoids determines JNK and IkappaB regulation in Toll-like receptor-stimulated macrophages. Blood 115, 1921–1931. Search in Google Scholar

Biddie, S.C., John, S., Sabo, P.J., Thurman, R.E., Johnson, T.A., Schiltz, R.L., Miranda, T.B., Sung, M.H., Trump, S., Lightman, S.L., et al. (2011). Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155. Search in Google Scholar

Bledsoe, R.K., Montana, V.G., Stanley, T.B., Delves, C.J., Apolito, C.J., McKee, D.D., Consler, T.G., Parks, D.J., Stewart, E.L., Willson, T.M., et al. (2002). Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110, 93–105. Search in Google Scholar

Chen, D., Ma, H., Hong, H., Koh, S.S., Huang, S.M., Schurter, B.T., Aswad, D.W., and Stallcup, M.R. (1999). Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177. Search in Google Scholar

Clark, A.R. (2007). Anti-inflammatory functions of glucocorticoid-induced genes. Mol. Cell. Endocrinol. 275, 79–97. Search in Google Scholar

Clark, A.R. and Lasa, M. (2003). Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways. Curr. Opin. Pharmacol. 3, 404–411. Search in Google Scholar

De Bosscher, K., Haegeman, G., and Elewaut, D. (2010). Targeting inflammation using selective glucocorticoid receptor modulators. Curr. Opin. Pharmacol. 10, 497–504. Search in Google Scholar

Finan, B., Yang, B., Ottaway, N., Stemmer, K., Muller, T.D., Yi, C.X., Habegger, K., Schriever, S.C., Garcia-Caceres, C., Kabra, D.G., et al. (2012). Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856. Search in Google Scholar

Flammer, J.R., Dobrovolna, J., Kennedy, M.A., Chinenov, Y., Glass, C.K., Ivashkiv, L.B., and Rogatsky, I. (2010). The type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol. Cell. Biol. 30, 4564–4574. Search in Google Scholar

Frijters, R., Fleuren, W., Toonen, E.J., Tuckermann, J.P., Reichardt, H.M., van der Maaden, H., van Elsas, A., van Lierop, M.J., Dokter, W., de Vlieg, J. et al. (2010). Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics 11, 359. Search in Google Scholar

Gebhardt, J.C., Suter, D.M., Roy, R., Zhao, Z.W., Chapman, A.R., Basu, S., Maniatis, T., and Xie, X.S. (2013). Single-molecule imaging of transcription factor binding to DNA in live mammalian cells. Nat. Methods 10, 421–426. Search in Google Scholar

Granfeldt, A., Hvas, C.L., Graversen, J.H., Christensen, P.A., Petersen, M.D., Anton, G., Svendsen, P., Solling, C., Etzerodt, A., Tonnesen, E., et al. (2013). Targeting dexamethasone to macrophages in a porcine endotoxemic model. Crit. Care Med. 41, E309–E318. Search in Google Scholar

Grontved, L., John, S., Baek, S., Liu, Y., Buckley, J.R., Vinson, C., Aguilera, G., and Hager, G.L. (2013). C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J. 32, 1568–1583. Search in Google Scholar

Hammer, M., Echtenachter, B., Weighardt, H., Jozefowski, K., Rose-John, S., Mannel, D.N., Holzmann, B., and Lang, R. (2010). Increased inflammation and lethality of Dusp1-/- mice in polymicrobial peritonitis models. Immunology 131, 395–404. Search in Google Scholar

Hannon, R., Croxtall, J.D., Getting, S.J., Roviezzo, F., Yona, S., Paul-Clark, M.J., Gavins, F.N., Perretti, M., Morris, J.F., Buckingham, J.C. et al. (2003). Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse. FASEB J. 17, 253–255. Search in Google Scholar

Heck, S., Kullmann, M., Gast, A., Ponta, H., Rahmsdorf, H.J., Herrlich, P., and Cato, A.C.B. (1994). A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor Ap-1. EMBO J. 13, 4087–4095. Search in Google Scholar

Hübner, S. and Tuckermann, J. (2012). Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice. Biomol. Concepts 3, 241–253. Search in Google Scholar

Jewell, C.M., Scoltock, A.B., Hamel, B.L., Yudt, M.R., and Cidlowski, J.A. (2012). Complex human glucocorticoid receptor dim mutations define glucocorticoid induced apoptotic resistance in bone cells. Mol. Endocrinol. 26, 244–256. Search in Google Scholar

John, S., Sabo, P.J., Thurman, R.E., Sung, M.H., Biddie, S.C., Johnson, T.A., Hager, G.L., and Stamatoyannopoulos, J.A. (2011). Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43, 264–268. Search in Google Scholar

Kino, T., Manoli, I., Kelkar, S., Wang, Y., Su, Y.A., and Chrousos, G.P. (2009). Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity. Biochem. Biophys. Res. Commun. 381, 671–675. Search in Google Scholar

Kleiman, A. and Tuckermann, J.P. (2007). Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice. Mol. Cell. Endocrinol. 275, 98–108. Search in Google Scholar

Kleiman, A., Hübner, S., Rodriguez Parkitna, J.M., Neumann, A., Hofer, S., Weigand, M.A., Bauer, M., Schmid, W., Schutz, G., Libert, C., et al. (2012). Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages. FASEB J. 26, 722–729. Search in Google Scholar

Lim H., Uhlenhaut N.H., Rauch A., Weiner J., Hübner S., Hübner N., Won J., Lazar M.A., Tuckermann, J., and Steger D.J. (2015). Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. in press. Search in Google Scholar

Ma, H., Baumann, C.T., Li, H., Strahl, B.D., Rice, R., Jelinek, M.A., Aswad, D.W., Allis, C.D., Hager, G.L., and Stallcup, M.R. (2001). Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr. Biol. 11, 1981–1985. Search in Google Scholar

Meijsing, S.H., Pufall, M.A., So, A.Y., Bates, D.L., Chen, L., and Yamamoto, K.R. (2009). DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324, 407–410. Search in Google Scholar

Nicolaides, N.C., Galata, Z., Kino, T., Chrousos, G.P., and Charmandari, E. (2010). The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75, 1–12. Search in Google Scholar

Nixon, M., Andrew, R., and Chapman, K.E. (2013). It takes two to tango: dimerisation of glucocorticoid receptor and its anti-inflammatory functions. Steroids 78, 59–68. Search in Google Scholar

Oakley, R.H. and Cidlowski, J.A. (2011). Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J. Biol. Chem. 286, 3177–3184. Search in Google Scholar

Pinheiro, I., Dejager, L., Petta, I., Vandevyver, S., Puimege, L., Mahieu, T., Ballegeer, M., Van Hauwermeiren, F., Riccardi, C., Vuylsteke, M. et al. (2013). LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome. EMBO Mol. Med. 5, 456–470. Search in Google Scholar

Presman, D.M., Ogara, M.F., Stortz, M., Alvarez, L.D., Pooley, J.R., Schiltz, R.L., Grontved, L., Johnson, T.A., Mittelstadt, P.R., Ashwell, J.D., et al. (2014). Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor. PLoS Biol. 12, e1001813. Search in Google Scholar

Rao, N.A., McCalman, M.T., Moulos, P., Francoijs, K.J., Chatziioannou, A., Kolisis, F.N., Alexis, M.N., Mitsiou, D.J., and Stunnenberg, H.G. (2011). Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res. 21, 1404–1416. Search in Google Scholar

Rapicavoli, N.A., Qu, K., Zhang, J.J., Mikhail, M., Laberge, R.M., and Chang, H.Y. (2013). A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. eLife. 2, e00762. Search in Google Scholar

Ratman, D., Vanden Berghe, W., Dejager, L., Libert, C., Tavernier, J., Beck, I.M., and De Bosscher, K. (2013). How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol. Cell. Endocrinol. 380, 41–54. Search in Google Scholar

Rauch, A., Seitz, S., Baschant, U., Schilling, A.F., Illing, A., Stride, B., Kirilov, M., Mandic, V., Takacz, A., Schmidt-Ullrich, R., et al. (2010). Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab. 11, 517–531. Search in Google Scholar

Reddy, T.E., Pauli, F., Sprouse, R.O., Neff, N.F., Newberry, K.M., Garabedian, M.J., and Myers, R.M. (2009). Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res. 19, 2163–2171. Search in Google Scholar

Reichardt, H.M., Kaestner, K.H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P. et al. (1998). DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541. Search in Google Scholar

Reichardt, H.M., Tuckermann, J.P., Gottlicher, M., Vujic, M., Weih, F., Angel, P., Herrlich, P., and Schutz, G. (2001). Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 20, 7168–7173. Search in Google Scholar

Rosenfeld, M.G., Lunyak, V.V., and Glass, C.K. (2006). Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428. Search in Google Scholar

Salojin, K.V., Owusu, I.B., Millerchip, K.A., Potter, M., Platt, K.A., and Oravecz, T. (2006). Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J. Immunol. 176, 1899–1907. Search in Google Scholar

Savory, J.G., Prefontaine, G.G., Lamprecht, C., Liao, M., Walther, R.F., Lefebvre, Y.A., and Hache, R.J. (2001). Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces. Mol. Cell. Biol. 21, 781–793. Search in Google Scholar

Schacke, H., Berger, M., Rehwinkel, H., and Asadullah, K. (2007). Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol. Cell Endocrinol. 275, 109–117. Search in Google Scholar

Schiller, B.J., Chodankar, R., Watson, L.C., Stallcup, M.R., and Yamamoto, K.R. (2014). Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes. Genome Biol. 15, 418. Search in Google Scholar

Schweingruber, N., Haine, A., Tiede, K., Karabinskaya, A., van den Brandt, J., Wust, S., Metselaar, J.M., Gold, R., Tuckermann, J.P., Reichardt, H.M., et al. (2011). Liposomal encapsulation of glucocorticoids alters their mode of action in the treatment of experimental autoimmune encephalomyelitis. J. Immunol. 187, 4310–4318. Search in Google Scholar

Schweingruber, N., Fischer, H.J., Fischer, L., van den Brandt, J., Karabinskaya, A., Labi, V., Villunger, A., Kretzschmar, B., Huppke, P., Simons, M., et al. (2014). Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses. Acta Neuropathol. 127, 713–729. Search in Google Scholar

Siersbaek, R., Nielsen, R., John, S., Sung, M.H., Baek, S., Loft, A., Hager, G.L., and Mandrup, S. (2011). Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis. EMBO J. 30, 1459–1472. Search in Google Scholar

Silverman, M.N., Mukhopadhyay, P., Belyavskaya, E., Tonelli, L.H., Revenis, B.D., Doran, J.H., Ballard, B.E., Tam, J., Pacher, P., and Sternberg, E.M. (2013). Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice. Mol. Psychiatry 18, 1006–1017. Search in Google Scholar

Starick, S.R., Ibn-Salem, J., Jurk, M., Hernandez, C., Love, M.I., Chung, H.R., Vingron, M., Thomas-Chollier, M., and Meijsing, S.H. (2015). ChIP-exo signal associated with DNA-binding motifs provide insights into the genomic binding of the glucocorticoid receptor and cooperating transcription factors. Genome Res. DOI:10.1101/gr.185157.114. Search in Google Scholar

Surjit, M., Ganti, K.P., Mukherji, A., Ye, T., Hua, G., Metzger, D., Li, M., and Chambon, P. (2011). Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145, 224–241. Search in Google Scholar

Tronche, F., Opherk, C., Moriggl, R., Kellendonk, C., Reimann, A., Schwake, L., Reichardt, H.M., Stangl, K., Gau, D., Hoeflich, A., et al. (2004). Glucocorticoid receptor function in hepatocytes is essential to promote postnatal body growth. Genes Dev. 18, 492–497. Search in Google Scholar

Tuckermann, J.P., Kleiman, A., Moriggl, R., Spanbroek, R., Neumann, A., Illing, A., Clausen, B.E., Stride, B., Forster, I., Habenicht, A.J., et al. (2007). Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J. Clin. Invest. 117, 1381–1390. Search in Google Scholar

Uhlenhaut, N.H., Barish, G.D., Yu, R.T., Downes, M., Karunasiri, M., Liddle, C., Schwalie, P., Hübner, N., and Evans, R.M. (2013). Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol. Cell 49, 158–171. Search in Google Scholar

Vandevyver, S., Dejager, L., and Libert, C. (2012a). On the trail of the glucocorticoid receptor: into the nucleus and back. Traffic 13, 364–374. Search in Google Scholar

Vandevyver, S., Dejager, L., Van Bogaert, T., Kleyman, A., Liu, Y., Tuckermann, J., and Libert, C. (2012b). Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. J. Clin. Invest. 122, 2130–2140. Search in Google Scholar

Vandevyver, S., Dejager, L., Tuckermann, J., and Libert, C. (2013). New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 154, 993–1007. Search in Google Scholar

Vandevyver, S., Dejager, L., and Libert, C. (2014). Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr. Rev. 35, 671–693. Search in Google Scholar

Voss, T.C., Schiltz, R.L., Sung, M.H., Yen, P.M., Stamatoyannopoulos, J.A., Biddie, S.C., Johnson, T.A., Miranda, T.B., John, S., and Hager, G.L. (2011). Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554. Search in Google Scholar

Waddell, D.S., Baehr, L.M., van den Brandt, J., Johnsen, S.A., Reichardt, H.M., Furlow, J.D., and Bodine, S.C. (2008). The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am. J. Physiol. Endocrinol. Metab. 295, E785–E797. Search in Google Scholar

Watson, L.C., Kuchenbecker, K.M., Schiller, B.J., Gross, J.D., Pufall, M.A., and Yamamoto, K.R. (2013). The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals. Nat. Struct. Mol. Biol. 20, 876–883. Search in Google Scholar

Yang, Y.H., Aeberli, D., Dacumos, A., Xue, J.R., and Morand, E.F. (2009). Annexin-1 regulates macrophage IL-6 and TNF via glucocorticoid-induced leucine zipper. J. Immunol. 183, 1435–1445. Search in Google Scholar

Zhao, Q., Wang, X., Nelin, L.D., Yao, Y., Matta, R., Manson, M.E., Baliga, R.S., Meng, X., Smith, C.V., Bauer, J.A., et al. (2006). MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med. 203, 131–140. Search in Google Scholar

Received: 2015-1-15
Accepted: 2015-4-13
Published Online: 2015-4-23
Published in Print: 2015-11-1

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