Glucocorticoid receptor dimerization is required for survival in septic shock
            <i>via</i>
            suppression of interleukin‐1 in macrophages

Kleiman, Anna; Hübner, Sabine; Parkitna, Jan Rodriguez; Neumann, Anita; Hofer, Stefan; Weigand, Markus A.; Bauer, Michael; Schmid, Wolfgang; Schütz, Günther; Libert, Claude; Reichardt, Holger M.; Tuckermann, Jan

doi:10.1096/fj.11-192112

Cited by 144 publications

(168 citation statements)

References 31 publications

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“…Therefore, propofol showed a significant anti-inflammatory effect, both in the previous and present studies. However, inflammation in the early stage of sepsis still had positive relevance for limiting sepsis spread and HPA axis activation (Min et al, 2011;Kleiman et al, 2012). Therefore, the timing propofol dosing to the peak of inflammation might be a better strategy than dosing immediately following surgery.…”

Section: Discussionmentioning

confidence: 99%

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Wang

Liu

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to determine the effect of etomidate and propofol pretreatment on the expression of glucocorticoid receptor and the prognosis of sepsis. The sepsis rat was used as a model. During glucocorticoid treatment, etomidate and propofol were applied alone or together at different time points. Survival curves, glucocorticoid receptor expression in the rat adrenal cortex, and inflammation levels were determined. The outcome of sepsis in rats was evaluated based on the combined utilization of propofol and etomidate. The results indicated that the combined utilization of propofol and etomidate pretreatment could significantly improve the effects of glucocorticoids on rat sepsis. Etomidate was shown to enhance the expression of the glucocorticoid receptor, while propofol was shown to inhibit the inflammatory response. Etomidate was best used immediately after modeling, whereas propofol was most suitable for use during the peak inflammatory reaction. These results demonstrated that anesthetics had 4741 Propofol and etomidate effects on GR in rats with sepsis ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4740-4748 (2015) the ability to enhance the effect of glucocorticoids in the treatment of sepsis. Etomidate was indicated for use in the early stage of inflammation to enhance expression of the glucocorticoid receptor, while propofol application was indicated at the peak of the inflammatory reaction owing to its strong anti-inflammation effect.

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Section: Discussionmentioning

confidence: 99%

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Wang

Liu

et al. 2015

Genet. Mol. Res.

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“…This mutant protein carries a single point mutation (A458T) that prevents it from forming dimers (20,21). Hence, GR dim/dim mice are largely devoid of TA induced by GR dimers and are more sensitive to inflammatory diseases, such as contact hypersensitivity and sepsis (22,23). These findings indicate that at least 1 GRE gene is induced by GR and has antiinflammatory functions in the GR dim/dim model, and perhaps in other models and diseases as well.…”

Section: Introductionmentioning

confidence: 91%

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Vandevyver¹,

Dejager²,

Bogaert³

et al. 2012

J. Clin. Invest.

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123

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Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation.Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1 -/-mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1 -/-mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1 -/-mice showed no change in sensitivity to TNF, Jnk2 -/-mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1 -/-and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.

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“…In agreement with the transactivation mechanism, GR dim mice show a reduced ability to activate transcription in the liver in response to exogenous ligands (Frijters et al 2010). However, later studies were inconsistent with expectations for transrepression by revealing that GR dim mice exhibit a diminished response to GC treatment in inflammatory paradigms such as TNF-induced inflammation (Vandevyver et al 2012), LPSand CLP-induced sepsis (Kleiman et al 2012;Silverman et al 2013), antigen-induced rheumatoid arthritis (Baschant et al 2011(Baschant et al , 2012, allergic contact dermatitis (Kleiman and Tuckermann 2007), and experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis (Schweingruber et al 2014). This was in part due to the inability of GR dim to induce GR-dependent antiinflammatory genes (Vandevyver et al 2012).…”

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confidence: 88%

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

et al. 2015

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Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding. Monomers colocalize with lineage-determining transcription factors in both liver and primary macrophages, and the GR half-site motif drives transcription, suggesting that monomeric binding is fundamental to GR's tissue-specific functions. In response to exogenous GC in vivo, GR dimers assemble on chromatin near ligand-activated genes, concomitant with monomer evacuation of sites near repressed genes. Thus, pharmacological GCs mediate gene expression by favoring GR homodimer occupancy at classic palindromic sites at the expense of monomeric binding. The findings have important implications for improving therapies that target GR.

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Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin‐1 in macrophages

Cited by 144 publications

References 31 publications

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Effects of propofol and etomidate pretreatment on glucocorticoid receptor expression following induction of sepsis in rats

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

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