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Glucocorticoids limit lipopolysaccharide‐induced lethal inflammation by a double control system
Author(s) -
Van Looveren Kelly,
Timmermans Steven,
Vanderhaeghen Tineke,
Wallaeys Charlotte,
Ballegeer Marlies,
Souffriau Jolien,
Eggermont Melanie,
Vandewalle Jolien,
Van Wyngene Lise,
De Bosscher Karolien,
Libert Claude
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949762
Subject(s) - library science , medicine , computer science
Lipopolysaccharides ( LPS ) can lead to a lethal endotoxemia, which is a systemic inflammatory response syndrome ( SIRS ) characterized by a systemic release of cytokines, such as TNF . Endotoxemia is studied intensely, as a model system of Gram‐negative infections. LPS ‐ and TNF ‐induced SIRS involve a strong induction of interferon‐stimulated genes ( ISG s), some of which cause cell death in the intestinal epithelium cells ( IEC s). It is well known that glucocorticoids ( GC s) protect against endotoxemia. By applying numerous mutant mouse lines, our data support a model whereby GC s, via their glucocorticoid receptor ( GR ), apply two key mechanisms to control endotoxemia, (i) at the level of suppression of TNF production in a GR monomer‐dependent way in macrophages and (ii) at the level of inhibition of TNFR 1‐induced ISG gene expression and necroptotic cell death mediators in IEC s in a GR dimer‐dependent way. Our data add new important insights to the understanding of the role of TNF in endotoxemia and the two separate key roles of GC s in suppressing TNF production and activity.