Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.
Glucocorticoids, which are widely used as antiinflammatory agents, downregulate the expression of the interleukin 6 gene and of additional cytokine genes involved in inflammatory responses. Conversely, the transcription factor NF-kappa B, a member of the Rel family of transcription factors, has been implicated in the induction of multiple genes involved ... in the early processes of immune and inflammatory responses. This prompted us to investigate whether one of the mechanisms by which glucocorticoids exert their antiinflammatory activities is through inhibition of gene activation mediated by NF-kappa B. We report that, in intact cells, activation of the interleukin 6 promoter by a combination of the factor NF-IL6 and the p65 subunit of NF-kappa B is inhibited by dexamethasone (ligand)-activated glucocorticoid receptor. Conversely, activation of the mouse mammary tumor virus promoter by a combination of dexamethasone and glucocorticoid receptor is inhibited by overexpression of p65. Furthermore, we provide evidence for physical association between glucocorticoid receptor and p65 in protein crosslinking and coimmunoprecipitation experiments, using either in vitro translated proteins or those present in cell extracts. These studies suggest that direct interactions between NF-kappa B and glucocorticoid receptor may partly account for the antiinflammatory properties of glucocorticoids in vivo.
Mesh Terms:
Base Sequence, Binding Sites, CCAAT-Enhancer-Binding Proteins, DNA, Complementary, DNA-Binding Proteins, Dexamethasone, Gene Expression Regulation, Hela Cells, Humans, Inflammation, Interleukin-1, Interleukin-6, Molecular Sequence Data, NF-kappa B, Nuclear Proteins, Promoter Regions, Genetic, Protein Conformation, Receptors, Glucocorticoid, Transcriptional Activation
Base Sequence, Binding Sites, CCAAT-Enhancer-Binding Proteins, DNA, Complementary, DNA-Binding Proteins, Dexamethasone, Gene Expression Regulation, Hela Cells, Humans, Inflammation, Interleukin-1, Interleukin-6, Molecular Sequence Data, NF-kappa B, Nuclear Proteins, Promoter Regions, Genetic, Protein Conformation, Receptors, Glucocorticoid, Transcriptional Activation
Proc. Natl. Acad. Sci. U.S.A.
Date: Jan. 18, 1994
PubMed ID: 8290595
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