Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

Bogaert, Tom Van; Vandevyver, Sofie; Dejager, Lien; Hauwermeiren, Filip Van; Pinheiro, Iris; Πέττα, Ιωάννα; Engblom, David; Kleyman, Anna; Schütz, Guenther; Tuckermann, Jan; Libert, Claude

doi:10.1074/jbc.m110.212365

Cited by 61 publications

(78 citation statements)

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“…The pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were shown to activate the HPA axis [37], thereby enhancing circulating glucocorticoids and exerting suppressive effects through GR activation. However, high levels of TNF-α have been associated with glucocorticoid resistance [38]. Upon excessive HPA activation, a downregulation of GR activity, probably caused by altered phosphorylation of the receptor and reduced protein stability [38,39], with concomitant glucocorticoid resistance has been observed, which may cause a shift from GR- to MR-mediated glucocorticoid effects.…”

Section: Discussionmentioning

confidence: 99%

“…However, high levels of TNF-α have been associated with glucocorticoid resistance [38]. Upon excessive HPA activation, a downregulation of GR activity, probably caused by altered phosphorylation of the receptor and reduced protein stability [38,39], with concomitant glucocorticoid resistance has been observed, which may cause a shift from GR- to MR-mediated glucocorticoid effects. GR blockade by administration of RU486 or elimination of glucocorticoids by adrenalectomy sensitized C57BL/6 mice to low-dose TNF-α [38].…”

Section: Discussionmentioning

confidence: 99%

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Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells

Chantong

Kratschmar

Nashev

et al. 2012

J Neuroinflammation

115

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BackgroundMicroglia, the resident macrophage-like cells in the brain, regulate innate immune responses in the CNS to protect neurons. However, excessive activation of microglia contributes to neurodegenerative diseases. Corticosteroids are potent modulators of inflammation and mediate their effects by binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Here, the coordinated activities of GR and MR on the modulation of the nuclear factor-κB (NF-κB) pathway in murine BV-2 microglial cells were studied.MethodsBV-2 cells were treated with different corticosteroids in the presence or absence of MR and GR antagonists. The impact of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was determined by incubating cells with 11-dehydrocorticosterone, with or without selective inhibitors. Expression of interleukin-6 (IL-6), tumor necrosis factor receptor 2 (TNFR2), and 11β-HSD1 mRNA was analyzed by RT-PCR and IL-6 protein expression by ELISA. NF-κB activation and translocation upon treatment with various corticosteroids were visualized by western blotting, immunofluorescence microscopy, and translocation assays.ResultsGR and MR differentially regulate NF-κB activation and neuroinflammatory parameters in BV-2 cells. By converting inactive 11-dehydrocorticosterone to active corticosterone, 11β-HSD1 essentially modulates the coordinated action of GR and MR. Biphasic effects were observed for 11-dehydrocorticosterone and corticosterone, with an MR-dependent potentiation of IL-6 and tumor necrosis factor-α (TNF-α) expression and NF-κB activation at low/moderate concentrations and a GR-dependent suppression at high concentrations. The respective effects were confirmed using the MR ligand aldosterone and the antagonist spironolactone as well as the GR ligand dexamethasone and the antagonist RU-486. NF-κB activation could be blocked by spironolactone and the inhibitor of NF-κB translocation Cay-10512. Moreover, an increased expression of TNFR2 was observed upon treatment with 11-dehydrocorticosterone and aldosterone, which was reversed by 11β-HSD1 inhibitors and/or spironolactone and Cay-10512.ConclusionsA tightly coordinated GR and MR activity regulates the NF-κB pathway and the control of inflammatory mediators in microglia cells. The balance of GR and MR activity is locally modulated by the action of 11β-HSD1, which is upregulated by pro-inflammatory mediators and may represent an important feedback mechanism involved in resolution of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells

Chantong

Kratschmar

Nashev

et al. 2012

J Neuroinflammation

115

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“…Thus, considering TNFa as a key mediator of adrenal crisis, glucocorticoid deficiency leads to both enhanced release of TNFa and enhanced sensitivity to TNFa. Furthermore, experimental evidence indicates that TNFa inhibits glucocorticoid receptor functions inducing a state of relative glucocorticoid resistance (60,61). In summary, lack of suppressive glucocorticoid activity can trigger adrenal crisis via enhanced TNFa secretion, enhanced TNFa sensitivity and TNFa-induced glucocorticoid resistance (Fig.…”

Section: Physiopathology Of Adrenal Crisismentioning

confidence: 99%

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Adrenal crisis

Allolio

2015

European Journal of Endocrinology

184

225

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Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5-10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis.

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“…In one study, dexamethasone completely prevented TNF-induced SIRS, but was no longer protective when given 6h-8h after TNF challenge, suggesting the establishment of a quick GC resistance after TNF [119]. Also in numerous other models of acute, lethal inflammation, GCs protect when given in a close time frame compared to the challenge [170][171][172].…”

Section: Gcr In Sepsismentioning

confidence: 93%

“…A549) and immune cells [114][115][116][117][118]. In a mouse model of TNF-induced shock, TNF compromises the protective function of the GR by reducing the levels of both GR mRNA and protein [119].…”

Section: Gc Resistancementioning

confidence: 99%