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Science 13 October 1995:
Vol. 270. no. 5234, pp. 286 - 290
DOI: 10.1126/science.270.5234.286
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Reports

Immunosuppression by Glucocorticoids: Inhibition of NF-B Activity Through Induction of IB Synthesis

Nathalie Auphan (1),  Joseph A. DiDonato (2),  Caridad Rosette (2),  Arno Helmberg,  Michael Karin (3) (4)

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-kappaB) activation in mice and cultured cells. This inhibition is mediated by induction of the IkappaBalpha inhibitory protein, which traps activated NF-kappaB in inactive cytoplasmic complexes. Because NF-kappaB activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.

Department of Pharmacology, Program in Biomedical Sciences, Center for Molecular Genetics, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0636, USA.  
(1) Present address: Centre dÍmmunologie, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique, Marseille Laminy Case 906, 13288 Marseille, Cedex 9, France.  
(2) These authors contributed equally to this work.  
(3) Present address: Institute for General and Experimental Pathology, University of Innsbruck Medical School, A-6020 Innsbruck, Austria. 
(4) To whom correspondence should be addressed. 


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Glucocorticoid Ligands Specify Different Interactions with NF-{kappa}B by Allosteric Effects on the Glucocorticoid Receptor DNA Binding Domain.
H. Garside, A. Stevens, S. Farrow, C. Normand, B. Houle, A. Berry, B. Maschera, and D. Ray (2004)
J. Biol. Chem. 279, 50050-50059
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Guggulsterone Inhibits NF-{kappa}B and I{kappa}B{alpha} Kinase Activation, Suppresses Expression of Anti-apoptotic Gene Products, and Enhances Apoptosis.
S. Shishodia and B. B. Aggarwal (2004)
J. Biol. Chem. 279, 47148-47158
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Dobutamine Inhibits Phorbol-Myristate-Acetate-Induced Activation of Nuclear Factor-{kappa}B in Human T Lymphocytes In Vitro.
T. Loop, T. Bross, M. Humar, A. Hoetzel, R. Schmidt, H. L. Pahl, K. K. Geiger, and B. H. J. Pannen (2004)
Anesth. Analg. 99, 1508-1515
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Human breast milk suppresses the transcriptional regulation of IL-1{beta}-induced NF-{kappa}B signaling in human intestinal cells.
R. Minekawa, T. Takeda, M. Sakata, M. Hayashi, A. Isobe, T. Yamamoto, K. Tasaka, and Y. Murata (2004)
Am J Physiol Cell Physiol 287, C1404-C1411
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A Vitamin D Analog Down-Regulates Proinflammatory Chemokine Production by Pancreatic Islets Inhibiting T Cell Recruitment and Type 1 Diabetes Development.
N. Giarratana, G. Penna, S. Amuchastegui, R. Mariani, K. C. Daniel, and L. Adorini (2004)
J. Immunol. 173, 2280-2287
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Inhibition of aldose reductase attenuates TNF-{alpha}-induced expression of adhesion molecules in endothelial cells.
K. V. RAMANA, A. BHATNAGAR, and S. K. SRIVASTAVA (2004)
FASEB J 18, 1209-1218
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Pro- and Anti-Inflammatory Factors Cooperate to Control Hyaluronan Synthesis in Lung Fibroblasts.
T. S. Wilkinson, S. Potter-Perigo, C. Tsoi, L. C. Altman, and T. N. Wight (2004)
Am. J. Respir. Cell Mol. Biol. 31, 92-99
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Evidence for a Potent Antiinflammatory Effect of Rosiglitazone.
P. Mohanty, A. Aljada, H. Ghanim, D. Hofmeyer, D. Tripathy, T. Syed, W. Al-Haddad, S. Dhindsa, and P. Dandona (2004)
J. Clin. Endocrinol. Metab. 89, 2728-2735
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Interleukin-1 Receptor Antagonist Attenuates Airway Hyperresponsiveness Following Exposure to Ozone.
J.-W. Park, C. Taube, C. Swasey, T. Kodama, A. Joetham, A. Balhorn, K. Takeda, N. Miyahara, C. B. Allen, A. Dakhama, et al. (2004)
Am. J. Respir. Cell Mol. Biol. 30, 830-836
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Heparin-disaccharide affects T cells: inhibition of NF-{kappa}B activation, cell migration, and modulation of intracellular signaling.
I. Hecht, R. Hershkoviz, S. Shivtiel, T. Lapidot, I. R. Cohen, O. Lider, and L. Cahalon (2004)
J. Leukoc. Biol. 75, 1139-1146
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TGF-{beta}1 Represses Activation and Resultant Death of Microglia via Inhibition of Phosphatidylinositol 3-Kinase Activity.
W.-K. Kim, S.-Y. Hwang, E.-S. Oh, H. Z. Piao, K.-W. Kim, and I.-O. Han (2004)
J. Immunol. 172, 7015-7023
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Long-Term Alterations in Neuroimmune Responses after Neonatal Exposure to Lipopolysaccharide.
L. Boisse, A. Mouihate, S. Ellis, and Q. J. Pittman (2004)
J. Neurosci. 24, 4928-4934
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Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma.
A. Pastva, K. Estell, T. R. Schoeb, T. P. Atkinson, and L. M. Schwiebert (2004)
J. Immunol. 172, 4520-4526
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Glucocorticoid inhibition of SP-A gene expression in lung type II cells is mediated via the TTF-1-binding element.
J. L. Alcorn, K. N. Islam, P. P. Young, and C. R. Mendelson (2004)
Am J Physiol Lung Cell Mol Physiol 286, L767-L776
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Pretreatment with Dexamethasone Increases Antitumor Activity of Carboplatin and Gemcitabine in Mice Bearing Human Cancer Xenografts: In Vivo Activity, Pharmacokinetics, and Clinical Implications for Cancer Chemotherapy.
H. Wang, M. Li, J. J. Rinehart, and R. Zhang (2004)
Clin. Cancer Res. 10, 1633-1644
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Specific Inhibition of I{kappa}B Kinase Reduces Hyperalgesia in Inflammatory and Neuropathic Pain Models in Rats.
I. Tegeder, E. Niederberger, R. Schmidt, S. Kunz, H. Guhring, O. Ritzeler, M. Michaelis, and G. Geisslinger (2004)
J. Neurosci. 24, 1637-1645
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