title: Glucocorticoid-induced microRNA-511 protects against TNF by down-regulating TNFR1.
abstract: TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression.
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Puimège
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Steeland
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Ryckeghem
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: Vandewalle
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Lodens
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Vandevyver
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Staelens
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Timmermans
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium claude.libert@irc.vib-ugent.be.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D035683:MicroRNAs; C578472:Mirn511 microRNA, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha
keywords: TNF; glucocorticoids; miRs; receptor regulation; sepsis