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Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids
1Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain. wassim@agu.edu.bh
Journal of Molecular Endocrinology
|April 5, 2002
Summary
Glucocorticoids (GCs) reduce inflammation by inhibiting gene expression. They work by binding to cytosolic receptors (GRs), translocating to the nucleus, and modulating transcription factors like nuclear factor-kappaB (NF-kappaB).
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Glucocorticoids (GCs) are potent anti-inflammatory and antiproliferative agents.
- Their mechanism involves inhibiting cytokine and adhesion molecule expression.
- GCs interact with cytosolic receptors (GRs) leading to nuclear translocation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which GCs modulate gene transcription.
- To detail the interaction of activated GRs with DNA and transcription factors, particularly NF-kappaB.
- To understand how GCs influence transcriptional initiation and the assembly of transcription factor complexes.
Main Methods:
- Analysis of GR binding to Glucocorticoid Response Elements (GREs) in gene promoter regions.
- Investigation of GR interactions with NF-kappaB through various models (Simple, Composite, Transmodulation).
- Assessment of GR's effect on coactivator recruitment (e.g., CREB binding protein, p300) and pre-initiation complex assembly.
Main Results:
- Activated GRs bind to GREs, influencing the transcription of GC-responsive genes.
- GRs antagonize NF-kappaB activity via direct and indirect mechanisms, including IkappaB induction.
- GRs inhibit NF-kappaB transcriptional activity by interfering with DNA binding, protein-protein interactions, and coactivator recruitment.
Conclusions:
- GCs exert anti-inflammatory effects by modulating gene expression through GR activation.
- GRs significantly impact NF-kappaB signaling pathways, offering a key mechanism for GC action.
- GCs act proximally in the transcriptional process, inhibiting transcription factor assembly rather than affecting the pre-initiation complex.