Glucocorticoids limit lipopolysaccharide‐induced lethal inflammation by a double control system

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.