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Cited by 242NF-κB Signaling PathwaysEstrogen and related hormone effectsSignaling Pathways in Disease

Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

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Almawi, WY, Melemedjian, OK·2002·Journal of Molecular Endocrinology
DOI 10.1677/jme.0.0280069
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Abstract

Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-kappaB (NF-kappaB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-kappaB inhibitor, IkappaB. Activated GR also antagonized NF-kappaB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-kappaB binding to DNA (Simple Model), or association with NF-kappaB bound to the kappaB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of kappaB-bound NF-kappaB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-kappaB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-kappaB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.

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  • Prominent non-genomic examples include mRNA destabilization, competition for co-activators, and interference with the binding of transcription factors to DNA.

    “Prominent examples include mRNA destabilization, competition for co-activators [e.g., CREB-binding protein (CBP), p300, and GRIP], and interference with the binding of transcription factors to DNA (91–94).”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [91]

  • Liganded GRs impact gene transcription through non-genomic mechanisms that do not require de novo protein synthesis and underlie the more rapid actions of GCs.

    “In addition to their genomic actions, liganded GRs also impact on gene transcription through various non-genomic mechanisms. These mechanisms do not require de novo protein synthesis and thus underlie the more rapid actions of GCs.”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [91]

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Research works printed but not linked: 3

  1. Almawi WY, Saouda MS, Stevens AC, Lipman ML, Barth CM & Strom TB 1996b Partial mediation of glucocorticoid anti-proliferative effect by lipocortins. Journal of Immunology 156 3523-3529.
  2. Kleinert H, Euchenhofer C, Ihrig-Biedert I & Forstermann U 1996 Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-B. Journal of Pharmacology and Experimental Therapeutics 49 15-21.
  3. Newton R, Hart LA, Stevens DA, Bergmann M, Donnelly LE, Adcock IM & Barnes PJ 1998 Effect of dexamethasone on interleukin-1 -(IL-1 )-induced nuclear factor-B (NF-B) and B-dependent transcription in epithelial cells. European Journal of Biochemistry 254 81-89.

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Authors
Almawi, W., & Melemedjian, O.
Affiliations
Arabian Gulf University (BH)
Venue
Journal of Molecular Endocrinology
Publisher
Bioscientifica
Published
2002-04-01
Volume
28
Issue
2
Pages
69-78
ISSN
  • 0952-5041 (ISSN-L)
  • 1479-6813
DOI
10.1677/jme.0.0280069
OpenAlex
W2157744411
Cited by
242
References
74
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 11 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 10 · 2012: 9
FWCI
1.75
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
glucocorticoids, glucocorticoid receptor, NF-κB, negative transcriptional regulation, IκB, glucocorticoid response element, protein-protein interaction, CREB-binding protein, P300, transcription initiation, anti-inflammatory activity, cytokine expression
MeSH terms
Animals, Binding, Competitive, Cell Division, Glucocorticoids, Humans, Models, Biological, Protein Binding, T-Lymphocytes, NF-kappa B

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