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| Status |
Public on Apr 26, 2018 |
| Title |
Glucocorticoid receptor dimers control intestinal STAT1-mediated IFN- and TNF-induced inflammation in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tumor Necrosis Factor (TNF) is an important mediator in numerous inflammatory diseases, e.g. in inflammatory bowel diseases (IBD). 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 significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong interferon-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 between gut microbiota, interferons, necroptosis and GR in both the basal response to acute inflammatory challenges and in the pharmacological intervention by GCs.
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| Overall design |
30 samples in 2 sequencing experiments (24 + 6): 24 samples (1-24) in 2 groups with 4 conditions/group and 3 biological replicates/condition 6 samples (25-30) in 2 conditions with 3 biological replicates/condition
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| Contributor(s) |
Ballegeer M, Van Looveren K, Timmermans S, Eggermont M, Vandevyver S, Thery F, Dendocker K, Souffriau J, Vandewalle J, Van Wyngene L, De Rycke R, Takahashi N, Vandenabeele P, Tuckermann J, Reichardt HM, Impens F, Beyaert R, De Bosscher K, Vandenbroucke RE, Libert C |
| Citation(s) |
29746256, 32383538 |
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| Submission date |
Apr 25, 2018 |
| Last update date |
Jun 10, 2020 |
| Contact name |
Steven Timmermans |
| Organization name |
VIB-UGent
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| Street address |
Technologiepark 71
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| City |
Gent |
| ZIP/Postal code |
9052 |
| Country |
Belgium |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA453622 |
| SRA |
SRP142645 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE113691_RAW.tar |
4.5 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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