Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era

Gerber, Anthony N.; Newton, Robert; Sasse, Sarah K.

doi:10.1016/j.jbc.2021.100687

Cited by 33 publications

(31 citation statements)

References 148 publications

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“…Within the context of airway disease, GR affects several genes and pathways associated with inflammation and metabolic processes [ 151 ]. The current model by which GR is thought to suppress inflammation involves modulating chromatin structure, suppressing promoter activity at pro-inflammatory genes, and enhancing the expression of anti-inflammatory mediators [ 152 , 153 ]. The wide-ranging anti-inflammatory effects of corticosteroids are centered on their ability to modulate gene expression in multiple cell types, including immune cells, epithelium, smooth muscle, and fibroblasts.…”

Section: Oxidative Stress Promotes Corticosteroid Insensitivitymentioning

confidence: 99%

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

et al. 2021

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Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.

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Section: Oxidative Stress Promotes Corticosteroid Insensitivitymentioning

confidence: 99%

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

et al. 2021

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“…First, GCs induce the transcription of IkBa, A20, DUSP1, and GILZ, negative regulators of NF-kB and AP-1, which inhibits macrophage activation by LPS (26). Second, GC-induced transcription might snatch transcriptional coactivators and chromatin remodeling factors from the enhancers in target genes of inflammatory cytokines and reduce their transcription (2).…”

Section: Production and Action Of Gcsmentioning

confidence: 99%

“…Moreover, GR rapidly changed the accessibility of TNF-induced gene enhancers. Based on these observations, Gerber et al proposed the squelching model that GR binding to GREs might snatch transcriptional coactivators and chromatin remodeling factors from the enhancers of TNF-induced genes and reduce their transcription of the TNF-induced genes (2). Taken together, transcriptional regulation mediated by GR is highly diversified.…”

Section: Regulation Of Immune-related Gene Expression By Grmentioning

confidence: 99%

“…GCs not only regulate functions of the brain, liver, muscle, and bone, they also exert immunoregulatory effects (1). In general, they have strong anti-inflammatory and immunosuppressive effects and are commonly used to treat allergies, autoimmunity conditions, and inflammation by suppressing the expression of inflammatory cytokines, increasing immunosuppressive proteins, and inducing the apoptosis of lymphocytes (1)(2)(3). Especially, GCs strongly inhibit cell-mediated immune responses against cancer and infection (4-6).…”

Section: Introductionmentioning

confidence: 99%

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Pleiotropic Effects of Glucocorticoids on the Immune System in Circadian Rhythm and Stress

2021

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Glucocorticoids (GCs) are a class of steroid hormones secreted from the adrenal cortex. Their production is controlled by circadian rhythm and stress, the latter of which includes physical restraint, hunger, and inflammation. Importantly, GCs have various effects on immunity, metabolism, and cognition, including pleiotropic effects on the immune system. In general, GCs have strong anti-inflammatory and immunosuppressive effects. Indeed, they suppress inflammatory cytokine expression and cell-mediated immunity, leading to increased risks of some infections. However, recent studies have shown that endogenous GCs induced by the diurnal cycle and dietary restriction enhance immune responses against some infections by promoting the survival, redistribution, and response of T and B cells via cytokine and chemokine receptors. Furthermore, although GCs are reported to reduce expression of Th2 cytokines, GCs enhance type 2 immunity and IL-17-associated immunity in some stress conditions. Taken together, GCs have both immunoenhancing and immunosuppressive effects on the immune system.

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“…However, with reduced transcriptional activity, GR monomers can indeed bind several transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription 3 (STAT3) and activator protein-1 (AP-1) [ 10 , 11 ] and thus the Gr dim/dim model can allow discriminating between GR activity as dimer or monomer.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription

Dinarello

Tesoriere

Martini

et al. 2022

IJMS

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Glucocorticoids mainly exert their biological functions through their cognate receptor, encoded by the nr3c1 gene. Here, we analysed the glucocorticoids mechanism of action taking advantage of the availability of different zebrafish mutant lines for their receptor. The differences in gene expression patterns between the zebrafish gr knock-out and the grs357 mutant line, in which a point mutation prevents binding of the receptor to the hormone-responsive elements, reveal an intricate network of GC-dependent transcription. Particularly, we show that Stat3 transcriptional activity mainly relies on glucocorticoid receptor GR tethering activity: several Stat3 target genes are induced upon glucocorticoid GC exposure both in wild type and in grs357/s357 larvae, but not in gr knock-out zebrafish. To understand the interplay between GC, their receptor, and the mineralocorticoid receptor, which is evolutionarily and structurally related to the GR, we generated an mr knock-out line and observed that several GC-target genes also need a functional mineralocorticoid receptor MR to be correctly transcribed. All in all, zebrafish mutants and transgenic models allow in vivo analysis of GR transcriptional activities and interactions with other transcription factors such as MR and Stat3 in an in-depth and rapid way.

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Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era

Cited by 33 publications

References 148 publications

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

Pleiotropic Effects of Glucocorticoids on the Immune System in Circadian Rhythm and Stress

Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription

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