GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology

Thiagarajah, Angeline Sharmila; Eades, Laura; Thomas, Prabakar Rajan; Guymer, Emma Kathryn; Morand, Eric Francis; Clarke, David M.; Leech, Michelle

doi:10.1016/j.brainres.2014.06.008

Cited by 28 publications

(20 citation statements)

References 83 publications

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“…Moderate intake relieves stresses and produces pleasure, while heavy drinking induces mood and psychological abnormalities, such as depression. GILZ over-expression is found to be associated with depression (71,72). Our data clearly demonstrated that short-chain alcohols upregulate GILZ, which may serve as a critical mechanism for alcohol mood regulation and alcohol-precipitated depression.…”

Section: Discussionsupporting

confidence: 53%

Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response

Jennings

Nelson

et al. 2020

Front. Immunol.

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Alcohol differentially affects human health, depending on the pattern of exposure. Moderate intake provides beneficial mood modulation and an anti-inflammatory effect, while excessive consumption leads to immunosuppression and various alcohol use disorders. The mechanism underlying this bi-phasic action mode of alcohol has not been clearly defined. Our previous publication demonstrated that ethanol, in the absence of glucocorticoids (GCs), induces expression of Glucocorticoid-Induced Leucine Zipper (GILZ), a key molecule that transduces GC anti-inflammatory effect through a non-canonical activation of glucocorticoid receptor (1). Here we report that similar short-chain alcohols, such as ethanol, propanol and isopropanol, share the same property of upregulating GILZ gene expression, and blunt cell inflammatory response in vitro. When mice were exposed to these alcohols, GILZ gene expression in immune cells was augmented in a dose-dependent manner. Monocytes and neutrophils were most affected. The short-chain alcohols suppressed host inflammatory response to lipopolysaccharide (LPS) and significantly reduced LPS-induced mortality. Intriguingly, propanol and isopropanol displayed more potent protection than ethanol at the same dose. Inhibition of ethanol metabolism enhanced the ethanol protective effect, suggesting that it is ethanol, not its derivatives or metabolites, that induces immune suppression. Taken together, short-chain alcohols per se upregulate GILZ gene expression and provide immune protection against LPS toxicity, suggesting a potential measure to counter LPS septic shock in a resource limited situation.

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Section: Discussionsupporting

confidence: 53%

Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response

Jennings

Nelson

et al. 2020

Front. Immunol.

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“…Furthermore, we found a correlation between NR3C1 levels and TSC22D3 mRNA up-regulation. This result reinforces the fact that GILZ expression was proposed as a reliable measure of GR function [ 33 ]. We also demonstrated that GILZ silencing induced a strong reduction in Dex-induced cell death.…”

Section: Discussionsupporting

confidence: 86%

Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

Kervoëlen

Ménoret²,

Gomez‐Bougie

et al. 2015

Oncotarget

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Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoidinduced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti-and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects.

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“…Our results imply that, in the chronic stress response, miR-15a and its target FKBP51 represent major components for the following reasons: Although miR-15a is bioinformatically predicted to target other stress- and depression/anxiety-related transcripts, such as GILZ or Sgk1 (Anacker et al., 2013, Thiagarajah et al., 2014), the mRNA levels of these genes were unchanged in our Ago2 IP array (data not shown), supporting the specificity of the assay. In the present study, we focused exclusively on miR-15a regulation of FKBP51 due to the reported involvement of this gene in stress-response regulation and stress-linked psychopathologies (Hartmann et al., 2012, Hartmann et al., 2015, Scharf et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress

et al. 2016

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SummaryMicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15a in stress adaptation and the pathogenesis of stress-related psychopathologies.

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GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology

Cited by 28 publications

References 83 publications

Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response

Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response

Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress

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