help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vayssière, B. M.
Right arrow Articles by Resche-Rigon, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vayssière, B. M.
Right arrow Articles by Resche-Rigon, M.
Molecular Endocrinology 11 (9): 1245-1255
Copyright © 1997 by The Endocrine Society

Synthetic Glucocorticoids That Dissociate Transactivation and AP-1 Transrepression Exhibit Antiinflammatory Activity in Vivo

Béatrice M. Vayssière1, Sonia Dupont2, Agnès Choquart, Francis Petit, Teresa Garcia, Christian Marchandeau, Hinrich Gronemeyer and Michèle Resche-Rigon

Roussel UCLAF (B.M.V., S.D., A.C., F.P., T.G., C.M., M.R.-R.) 93235 Romainville Cedex, France
Institut de Génétique et de Biologie Moléculaire et Cellulaire (H.G.) IGBMC-BP. 163 67404 Illkirch Cedex, C.U. de Strasbourg, France

Some of the most potent antiinflammatory and immunosuppressive agents are synthetic glucocorticoids. However, major side effects severely limit their therapeutic use. The development of improved glucocorticoid-based drugs will require the separation of beneficial from deleterious effects. One possibility toward this goal is to try to dissociate two main activities of glucocorticoids, i.e. transactivation and transrepression. Screening of a library of compounds using transactivation and AP-1 transrepression models in transiently transfected cells identified dissociated glucocorticoids, which exert strong AP-1 inhibition but little or no transactivation. Importantly, despite high ligand binding affinity, the prototypic dissociated compound, RU24858, acted as a weak agonist and did not efficiently antagonize dexamethasone-induced transcription in transfected cells. Similar results were obtained in hepatic HTC cells for the transactivation of the endogenous tyrosine amino transferase gene (TAT), which encodes one of the enzymes involved in the glucocorticoid-dependent stimulation of neoglucogenesis. To investigate whether dissociated glucocorticoids retained the antiinflammatory and immunosuppressive potential of classic glucocorticoids, several in vitro and in vivo models were used. Indeed, secretion of the proinflammatory lymphokine interleukin-1ß was severely inhibited by dissociated glucocorticoids in human monocytic THP 1 cells. Moreover, in two in vivo models, these compounds exerted an antiinflammatory and immunosuppressive activity as potent as that of the classic glucocorticoid prednisolone. These results may lead to an improvement of antiinflammatory and immunosuppressive therapies and provide a novel concept for drug discovery.




This article has been cited by other articles:


Home page
 Mol. Endocrinol.Home page
K. De Bosscher and G. Haegeman
Minireview: Latest Perspectives on Antiinflammatory Actions of Glucocorticoids
Mol. Endocrinol., March 1, 2009; 23(3): 281 - 291.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
F. J. Lopez, R. J. Ardecky, B. Bebo, K. Benbatoul, L. De Grandpre, S. Liu, M. D. Leibowitz, K. Marschke, J. Rosen, D. Rungta, et al.
LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo
Endocrinology, May 1, 2008; 149(5): 2080 - 2089.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
M. Kaur, J. E. Chivers, M. A. Giembycz, and R. Newton
Long-Acting 2-Adrenoceptor Agonists Synergistically Enhance Glucocorticoid-Dependent Transcription in Human Airway Epithelial and Smooth Muscle Cells
Mol. Pharmacol., January 1, 2008; 73(1): 203 - 214.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. N. Miner, B. Ardecky, K. Benbatoul, K. Griffiths, C. J. Larson, D. E. Mais, K. Marschke, J. Rosen, E. Vajda, L. Zhi, et al.
Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein protein interaction profile
PNAS, December 4, 2007; 104(49): 19244 - 19249.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Newton and N. S. Holden
Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor?
Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809.
[Abstract] [Full Text] [PDF]

Home page
 Exp PhysiolHome page
A. McMaster and D. W. Ray
Modelling the glucocorticoid receptor and producing therapeutic agents with anti-inflammatory effects but reduced side-effects
Exp Physiol, March 1, 2007; 92(2): 299 - 309.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. I. Castillo, R. Sanchez-Martinez, A. M. Jimenez-Lara, A. Steinmeyer, U. Zugel, and A. Aranda
Characterization of Vitamin D Receptor Ligands with Cell-Specific and Dissociated Activity
Mol. Endocrinol., December 1, 2006; 20(12): 3093 - 3104.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. E. Chivers, W. Gong, E. M. King, J. Seybold, J. C. Mak, L. E. Donnelly, N. S. Holden, and R. Newton
Analysis of the Dissociated Steroid RU24858 Does Not Exclude a Role for Inducible Genes in the Anti-Inflammatory Actions of Glucocorticoids
Mol. Pharmacol., December 1, 2006; 70(6): 2084 - 2095.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P. J. Barnes
Corticosteroid effects on cell signalling
Eur. Respir. J., February 1, 2006; 27(2): 413 - 426.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. De Bosscher, W. V. Berghe, I. M. E. Beck, W. Van Molle, N. Hennuyer, J. Hapgood, C. Libert, B. Staels, A. Louw, and G. Haegeman
A fully dissociated compound of plant origin for inflammatory gene repression
PNAS, November 1, 2005; 102(44): 15827 - 15832.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. Rosen and J. N. Miner
The Search for Safer Glucocorticoid Receptor Ligands
Endocr. Rev., May 1, 2005; 26(3): 452 - 464.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
K. Biggadike, I. Uings, and S. N. Farrow
Designing Corticosteroid Drugs for Pulmonary Selectivity
Proceedings of the ATS, December 1, 2004; 1(4): 352 - 355.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
G. Hochhaus
New Developments in Corticosteroids
Proceedings of the ATS, November 1, 2004; 1(3): 269 - 274.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. Desmet, P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau
Selective Blockade of NF-{kappa}B Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma
J. Immunol., November 1, 2004; 173(9): 5766 - 5775.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
O. Kassel, S. Schneider, C. Heilbock, M. Litfin, M. Gottlicher, and P. Herrlich
A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-{kappa}B-regulated promoters
Genes & Dev., October 15, 2004; 18(20): 2518 - 2528.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. E. Donnelly, R. Newton, G. E. Kennedy, P. S. Fenwick, R. H. F. Leung, K. Ito, R. E. K. Russell, and P. J. Barnes
Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms
Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L774 - L783.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Schacke, A. Schottelius, W.-D. Docke, P. Strehlke, S. Jaroch, N. Schmees, H. Rehwinkel, H. Hennekes, and K. Asadullah
Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects
PNAS, January 6, 2004; 101(1): 227 - 232.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
I. Kurucz, S. Toth, K. Nemeth, K. Torok, V. Csillik-Perczel, A. Pataki, C. Salamon, Z. Nagy, J. I. Szekely, K. Horvath, et al.
Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)
J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 83 - 92.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
P. J. Barnes and I. M. Adcock
How Do Corticosteroids Work in Asthma?
Ann Intern Med, September 2, 2003; 139(5_Part_1): 359 - 370.
[Full Text] [PDF]

Home page
 Endocr. Rev.Home page
K. De Bosscher, W. Vanden Berghe, and G. Haegeman
The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression
Endocr. Rev., August 1, 2003; 24(4): 488 - 522.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. Stevens, H. Garside, A. Berry, C. Waters, A. White, and D. Ray
Dissociation of Steroid Receptor Coactivator 1 and Nuclear Receptor Corepressor Recruitment to the Human Glucocorticoid Receptor by Modification of the Ligand-Receptor Interface: The Role of Tyrosine 735
Mol. Endocrinol., May 1, 2003; 17(5): 845 - 859.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. J. Coghlan, P. B. Jacobson, B. Lane, M. Nakane, C. W. Lin, S. W. Elmore, P. R. Kym, J. R. Luly, G. W. Carter, R. Turner, et al.
A Novel Antiinflammatory Maintains Glucocorticoid Efficacy with Reduced Side Effects
Mol. Endocrinol., May 1, 2003; 17(5): 860 - 869.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. He, D. Szapary, and S. S. Simons Jr.
Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation
J. Biol. Chem., December 13, 2002; 277(51): 49256 - 49266.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. Lasa, S. M. Abraham, C. Boucheron, J. Saklatvala, and A. R. Clark
Dexamethasone Causes Sustained Expression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase 1 and Phosphatase-Mediated Inhibition of MAPK p38
Mol. Cell. Biol., November 15, 2002; 22(22): 7802 - 7811.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
R. Korhonen, A. Lahti, M. Hamalainen, H. Kankaanranta, and E. Moilanen
Dexamethasone Inhibits Inducible Nitric-Oxide Synthase Expression and Nitric Oxide Production by Destabilizing mRNA in Lipopolysaccharide-Treated Macrophages
Mol. Pharmacol., September 1, 2002; 62(3): 698 - 704.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C. W. Lin, M. Nakane, M. Stashko, D. Falls, J. Kuk, L. Miller, R. Huang, C. Tyree, J. N. Miner, J. Rosen, et al.
trans-Activation and Repression Properties of the Novel Nonsteroid Glucocorticoid Receptor Ligand 2,5-Dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and Its Four Stereoisomers
Mol. Pharmacol., August 1, 2002; 62(2): 297 - 303.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Chen, S. Kaul, and S. S. Simons Jr.
Structure/Activity Elements of the Multifunctional Protein, GMEB-1. CHARACTERIZATION OF DOMAINS RELEVANT FOR THE MODULATION OF GLUCOCORTICOID RECEPTOR TRANSACTIVATION PROPERTIES
J. Biol. Chem., June 7, 2002; 277(24): 22053 - 22062.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Yoshikawa, Y. Makino, K. Okamoto, C. Morimoto, I. Makino, and H. Tanaka
Distinct Interaction of Cortivazol with the Ligand Binding Domain Confers Glucocorticoid Receptor Specificity. CORTIVAZOL IS A SPECIFIC LIGAND FOR THE GLUCOCORTICOID RECEPTOR
J. Biol. Chem., February 8, 2002; 277(7): 5529 - 5540.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. D. Baxter, P. Goede, J. W. Apriletti, B. L. West, W. Feng, K. Mellstrom, R. J. Fletterick, R. L. Wagner, P. J. Kushner, R. C. J. Ribeiro, et al.
Structure-Based Design and Synthesis of a Thyroid Hormone Receptor (TR) Antagonist
Endocrinology, February 1, 2002; 143(2): 517 - 524.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Miura, R. Ouchida, N. Yoshikawa, K. Okamoto, Y. Makino, T. Nakamura, C. Morimoto, I. Makino, and H. Tanaka
Functional Modulation of the Glucocorticoid Receptor and Suppression of NF-kappa B-dependent Transcription by Ursodeoxycholic Acid
J. Biol. Chem., December 7, 2001; 276(50): 47371 - 47378.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
K.F. Rabe and D.T. Schmidt
Pharmacological treatment of asthma today
Eur. Respir. J., July 2, 2001; 18(34_suppl): 34S - 40s.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
A. Aranda and A. Pascual
Nuclear Hormone Receptors and Gene Expression
Physiol Rev, July 1, 2001; 81(3): 1269 - 1304.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. KRAFT, Q. HAMID, G. P. CHROUSOS, R. J. MARTIN, and D. Y. M. LEUNG
Decreased Steroid Responsiveness at Night in Nocturnal Asthma . Is the Macrophage Responsible?
Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1219 - 1225.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
K. De Bosscher, W. Vanden Berghe, and G. Haegeman
Glucocorticoid Repression of AP-1 Is Not Mediated by Competition for Nuclear Coactivators
Mol. Endocrinol., February 1, 2001; 15(2): 219 - 227.
[Abstract] [Full Text]

Home page
 J. Immunol.Home page
M. G. Belvisi, S. L. Wicks, C. H. Battram, S. E. W. Bottoms, J. E. Redford, P. Woodman, T. J. Brown, S. E. Webber, and M. L. Foster
Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity
J. Immunol., February 1, 2001; 166(3): 1975 - 1982.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
M. V. Gonzalez, B. Jimenez, M. T. Berciano, J. M. Gonzalez-Sancho, C. Caelles, M. Lafarga, and A. Munoz
Glucocorticoids Antagonize AP-1 by Inhibiting the Activation/Phosphorylation of JNK Without Affecting its Subcellular Distribution
J. Cell Biol., September 5, 2000; 150(5): 1199 - 1208.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. JAFFUEL, P. DEMOLY, C. GOUGAT, P. BALAGUER, G. MAUTINO, P. GODARD, J. BOUSQUET, and M. MATHIEU
Transcriptional Potencies of Inhaled Glucocorticoids
Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 57 - 63.
[Abstract] [Full Text]

Home page
 ThoraxHome page
R. Newton
Molecular mechanisms of glucocorticoid action: what is important?
Thorax, July 1, 2000; 55(7): 603 - 613.
[Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. De Bosscher, W. Vanden Berghe, L. Vermeulen, S. Plaisance, E. Boone, and G. Haegeman
Glucocorticoids repress NF-kappa B-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell
PNAS, April 11, 2000; 97(8): 3919 - 3924.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
R. M. Sapolsky, L. M. Romero, and A. U. Munck
How Do Glucocorticoids Influence Stress Responses? Integrating Permissive, Suppressive, Stimulatory, and Preparative Actions
Endocr. Rev., February 1, 2000; 21(1): 55 - 89.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
D. Luo, E. Guerin, M.-G. Ludwig, I. Stoll, P. Basset, and P. Anglard
Transcriptional Induction of Stromelysin-3 in Mesodermal Cells Is Mediated by an Upstream CCAAT/Enhancer-binding Protein Element Associated with a DNase I-hypersensitive Site
J. Biol. Chem., December 24, 1999; 274(52): 37177 - 37185.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
K Thiele, A Bierhaus, F Autschbach, M Hofmann, W Stremmel, H Thiele, R Ziegler, and P P Nawroth
Cell specific effects of glucocorticoid treatment on the NF-kappa Bp65/Ikappa Balpha system in patients with Crohn's disease
Gut, November 1, 1999; 45(5): 693 - 704.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. M. Bamberger, T. Else, A.-M. Bamberger, F. Ulrich Beil, and H. M. Schulte
Dissociative Glucocorticoid Activity of Medroxyprogesterone Acetate in Normal Human Lymphocytes
J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4055 - 4061.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
D. W. Ray, C.-S. Suen, A. Brass, J. Soden, and A. White
Structure/Function of the Human Glucocorticoid Receptor: Tyrosine 735 Is Important for Transactivation
Mol. Endocrinol., November 1, 1999; 13(11): 1855 - 1863.
[Abstract] [Full Text]

Home page
 Mol. Pharmacol.Home page
W. Vanden Berghe, E. Francesconi, K. De Bosscher, M. Resche-Rigon, and G. Haegeman
Dissociated Glucocorticoids with Anti-Inflammatory Potential Repress Interleukin-6 Gene Expression by a Nuclear Factor-kappa B-Dependent Mechanism
Mol. Pharmacol., October 1, 1999; 56(4): 797 - 806.
[Abstract] [Full Text]

Home page
 Mol. Pharmacol.Home page
O. Kassel, F. Schmidlin, C. Duvernelle, F. de Blay, and N. Frossard
Up- and Down-Regulation by Glucocorticoids of the Constitutive Expression of the Mast Cell Growth Factor Stem Cell Factor by Human Lung Fibroblasts in Culture
Mol. Pharmacol., December 1, 1998; 54(6): 1073 - 1079.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
R. Newton, J. Seybold, L. M. E. Kuitert, M. Bergmann, and P. J. Barnes
Repression of Cyclooxygenase-2 and Prostaglandin E2 Release by Dexamethasone Occurs by Transcriptional and Post-transcriptional Mechanisms Involving Loss of Polyadenylated mRNA
J. Biol. Chem., November 27, 1998; 273(48): 32312 - 32321.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
S. Wakisaka, N. Suzuki, M. Takeno, Y. Takeba, H. Nagafuchi, N. Saito, H. Hashimoto, T. Tomita, T. Ochi, and T. Sakane
Involvement of simultaneous multiple transcription factor expression, including cAMP responsive element binding protein and OCT-1, for synovial cell outgrowth in patients with rheumatoid arthritis
Ann Rheum Dis, August 1, 1998; 57(8): 487 - 494.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
K. Ito, E. Jazrawi, B. Cosio, P. J. Barnes, and I. M. Adcock
p65-activated Histone Acetyltransferase Activity Is Repressed by Glucocorticoids. MIFEPRISTONE FAILS TO RECRUIT HDAC2 TO THE p65-HAT COMPLEX
J. Biol. Chem., August 3, 2001; 276(32): 30208 - 30215.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1997 by The Endocrine Society