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

Autor: Ballegeer M; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Van Looveren K; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Timmermans S; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Eggermont M; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Vandevyver S; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Thery F; VIB Center for Medical Biotechnology Ghent, Belgium.; Department of Biochemistry, Ghent University, Ghent, Belgium., Dendoncker K; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Souffriau J; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Vandewalle J; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Van Wyngene L; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., De Rycke R; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Takahashi N; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Vandenabeele P; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Tuckermann J; Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany., Reichardt HM; Institute for Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen, Germany., Impens F; VIB Center for Medical Biotechnology Ghent, Belgium.; Department of Biochemistry, Ghent University, Ghent, Belgium.; VIB Proteomics Core, VIB, Ghent, Belgium., Beyaert R; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., De Bosscher K; Department of Biochemistry, Ghent University, Ghent, Belgium.; Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, Ghent, Belgium., Vandenbroucke RE; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Libert C; VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2018 Aug 01; Vol. 128 (8), pp. 3265-3279. Date of Electronic Publication: 2018 Jun 25.
DOI: 10.1172/JCI96636
Abstrakt: 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.
Databáze: MEDLINE