Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.

Abstract

Glucocorticoids, which are widely used as anffinflammatory agents, downregulate the expression of the interleukin 6 gene and of additional cytokine genes involved in inflammatory responses. Conversely, the transcription factor NF-ucB, a member ofthe Rel family oftranscription 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 aninflammatory activities is through inhibition ofgene activation mediated by NF-KB. We report that, in intact cells, activation of the interieukin 6promoter by a combination of the factor NF-EL6 and the p65 subunit of NF-ucB 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-cB and glucocorticoid receptor may partly account for the antiinflammatory properties of glucocorticoids in vivo.

CAR is a cell–cell adhesion protein in human cancer cells and is expressionally modulated by dexamethasone, TNFα, and TGFβ

“…One of its anti-inflammatory mechanisms is brought about by inhibition of NF-kB activity via glucocorticoid receptor activation. 10 This study demonstrates that dexamethasone can reduce the expression level of CAR in various cancer cell lines, thereby reducing adenoviral transduction efficiency.…”

“…10 TNFa is a potent physiological activator of NF-kB. 21 We tested the effect of TNFa on the expression level of CAR and integrins in Figure 1 Influence of dexamethasone on adenoviral transgene expression.…”

Visualization of Glucocorticoid Receptor and Mineralocorticoid Receptor Interactions in Living Cells with GFP-Based Fluorescence Resonance Energy Transfer

“…Our results suggest that heterodimer formation between the GR and MR is required for corticosteroid-mediated transcription in the nuclear region but not essentially involved in the regulation of nuclear translocation of these receptors. Activated GR or MR may block the activity of other transcription factors, such as activator protein-1 and nuclear factor B, by direct protein-protein interaction rather than by dimer formation (Ray and Prefontaine, 1994;GuardiolaDiaz et al, 1996;Webster and Cidlowski, 1999). For such interactions to occur, the receptors may have the flexibility to exist as monomers in the nucleus under certain conditions.…”

Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia

“…23 In addition, the receptor modulates gene transcription by physically interacting with other transcription factors like AP-1 and NF-kB. 24,25 Many studies have been published describing the relation between clinical response and GRa expression in childhood lymphoblastic leukemia, but receptor expression levels appeared to be of limited clinical usefulness. [26][27][28][29] These observations have led many researchers to believe that clinical resistance to GCs should be sought further downstream in the GC lytic pathway.…”