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Research ArticleArticle

Dissociated Glucocorticoids with Anti-Inflammatory Potential Repress Interleukin-6 Gene Expression by a Nuclear Factor-κB-Dependent Mechanism

Wim Vanden Berghe, Elisa Francesconi, Karolien De Bosscher, Michèle Resche-Rigon and Guy Haegeman
Molecular Pharmacology October 1999, 56 (4) 797-806;
Wim Vanden Berghe
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Elisa Francesconi
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Karolien De Bosscher
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Michèle Resche-Rigon
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Guy Haegeman
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Abstract

Synthetic glucocorticoids (GCs) remain among the most effective agents for the management of chronic inflammatory diseases. However, major side effects severely limit their therapeutic use. Physiologic and therapeutic activities of GCs are mediated by a nuclear receptor belonging to a superfamily of ligand-inducible transcription factors that, in addition to directly regulating their cognate gene programs, can also mutually interfere with other signaling pathways. We recently identified selective ligands of the glucocorticoid receptor that dissociate transactivation from activator protein 1 transrepression, and most importantly retain in vivo anti-inflammatory activity. To further document the mechanisms of action sustaining the observed in vivo activity, we report here on the interference of dissociated GCs with nuclear factor κB (NF-κB)-driven gene activation. We show that dissociated GCs repress tumor necrosis factor-induced interleukin-6 gene expression by an NF-κB-dependent mechanism, without changing the expression level of inhibitor κB. The DNA-binding activity of induced NF-κB also remained unchanged after stimulation of cells with the various compounds. Evidence for a direct nuclear mechanism of action was obtained by analysis of cell lines constitutively expressing a fusion protein between the DNA-binding domain of the yeast Gal4 protein and the transactivating p65 subunit of NF-κB, which was able to efficiently repress a Gal4-dependent luciferase reporter gene upon addition of the dissociated compounds. We therefore conclude that, in addition to dissociating transactivation from activator protein 1 transrepression, dissociated GCs mediate inhibition of NF-κB signaling by a mechanism that is independent of inhibitor κB induction.

Footnotes

  • Send reprint requests to: Dr. Michèle Resche-Rigon, Hoechst Marion Roussel, Molecular and Cellular Biology, Bone Disease Group, 102, route de Noisy, 93235 Romainville Cedex, France. E-mail:michele.resche-rigon{at}hmrag.com

  • 1 This work was supported by the Interuniversitaire Attractiepolen. G.H. is a Research Director with the Fonds voor Wetenschappelijk Onderzoek—Vlaanderen. K.D. holds a fellowship from the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie.

  • Abbreviations:
    GC
    glucocorticoid
    DBD
    DNA-binding domain
    DEX
    dexamethasone
    HTC
    hepatoma cell
    I-κB
    inhibitor κB
    NF-κB
    nuclear factor κB
    TNF
    tumor necrosis factor
    IL
    interleukin
    TRE
    tumor-promoting agent-responsive element
    GR
    glucocorticoid receptor
    NR
    nuclear receptor
    DMEM
    Dulbecco’s modified Eagle’s medium
    FCS
    fetal calf serum
    TBS
    Tris-buffered saline
    ELISA
    enzyme-linked immunosorbant assay
    ERK
    extracellular signal receptor-activated kinase
    MAPK
    mitogen-activated protein kinase
    AP-1
    activator protein 1
    GRE
    glucocorticoid-responsive element
    MMTV
    mouse mammary tumor virus
    ERK
    extracellular signal-regulated kinase
    • Received April 7, 1999.
    • Accepted June 24, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Dissociated Glucocorticoids with Anti-Inflammatory Potential Repress Interleukin-6 Gene Expression by a Nuclear Factor-κB-Dependent Mechanism

Wim Vanden Berghe, Elisa Francesconi, Karolien De Bosscher, Michèle Resche-Rigon and Guy Haegeman
Molecular Pharmacology October 1, 1999, 56 (4) 797-806;

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Research ArticleArticle

Dissociated Glucocorticoids with Anti-Inflammatory Potential Repress Interleukin-6 Gene Expression by a Nuclear Factor-κB-Dependent Mechanism

Wim Vanden Berghe, Elisa Francesconi, Karolien De Bosscher, Michèle Resche-Rigon and Guy Haegeman
Molecular Pharmacology October 1, 1999, 56 (4) 797-806;
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