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Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice

Marlies Ballegeer (UGent) , Kelly Van Looveren (UGent) , Steven Timmermans (UGent) , Melanie Eggermont (UGent) , Sofie Vandevyver (UGent) , Fabien Thery (UGent) , Karen Dendoncker (UGent) , Jolien Souffriau (UGent) , Jolien Vandewalle (UGent) , Lise Van Wyngene (UGent) , et al.
(2018) JOURNAL OF CLINICAL INVESTIGATION. 128(8). p.3265-3279
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Abstract
TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.
Keywords
TUMOR-NECROSIS-FACTOR, TARGETED DISRUPTION, SIGNALING PATHWAY, EPITHELIAL-CELLS, GENE-EXPRESSION, BOWEL-DISEASE, ACTIVATION, INHIBITION, COMMENSAL, BETA

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Chicago
Ballegeer, Marlies, Kelly Van Looveren, Steven Timmermans, Melanie Eggermont, Sofie Vandevyver, Fabien Thery, Karen Dendoncker, et al. 2018. “Glucocorticoid Receptor Dimers Control Intestinal STAT1 and TNF-induced Inflammation in Mice.” Journal of Clinical Investigation 128 (8): 3265–3279.
APA
Ballegeer, M., Van Looveren, K., Timmermans, S., Eggermont, M., Vandevyver, S., Thery, F., Dendoncker, K., et al. (2018). Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice. JOURNAL OF CLINICAL INVESTIGATION, 128(8), 3265–3279.
Vancouver
1.
Ballegeer M, Van Looveren K, Timmermans S, Eggermont M, Vandevyver S, Thery F, et al. Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice. JOURNAL OF CLINICAL INVESTIGATION. 2018;128(8):3265–79.
MLA
Ballegeer, Marlies, Kelly Van Looveren, Steven Timmermans, et al. “Glucocorticoid Receptor Dimers Control Intestinal STAT1 and TNF-induced Inflammation in Mice.” JOURNAL OF CLINICAL INVESTIGATION 128.8 (2018): 3265–3279. Print.
@article{8581774,
  abstract     = {TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.},
  author       = {Ballegeer, Marlies and Van Looveren, Kelly and Timmermans, Steven and Eggermont, Melanie and Vandevyver, Sofie and Thery, Fabien and Dendoncker, Karen and Souffriau, Jolien and Vandewalle, Jolien and Van Wyngene, Lise and De Rycke, Riet and Takahashi, Nozomi and Vandenabeele, Peter and Tuckermann, Jan and Reichardt, Holger M and Impens, Francis and Beyaert, Rudi and De Bosscher, Karolien and Vandenbroucke, Roosmarijn and Libert, Claude},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  language     = {eng},
  number       = {8},
  pages        = {3265--3279},
  title        = {Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice},
  url          = {http://dx.doi.org/10.1172/jci96636},
  volume       = {128},
  year         = {2018},
}

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