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

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Lipopolysaccharides (LPS) trigger lethal endotoxemia, a systemic inflammatory response syndrome (SIRS) involving cytokine release like TNF.
• Endotoxemia serves as a model for Gram-negative infections, with LPS and TNF inducing interferon-stimulated genes (ISGs) that cause intestinal epithelial cell death.
• Glucocorticoids (GCs) are known to protect against endotoxemia.

Purpose of the Study:

• To elucidate the dual mechanisms by which GCs, via the glucocorticoid receptor (GR), control endotoxemia.
• To investigate the distinct roles of GR monomers and dimers in mediating GC protective effects.
• To understand the interplay between TNF, ISGs, and cell death in the context of endotoxemia and GC treatment.

Main Methods:

• Utilized numerous mutant mouse lines to dissect the functions of the glucocorticoid receptor (GR).
• Analyzed GR monomer-dependent suppression of TNF production in macrophages.
• Investigated GR dimer-dependent inhibition of TNFR1-induced ISG expression and necroptosis in intestinal epithelial cells (IECs).

Main Results:

• GCs employ two key GR-dependent mechanisms to control endotoxemia.
• Mechanism 1: GR monomer-dependent suppression of TNF production in macrophages.
• Mechanism 2: GR dimer-dependent inhibition of TNFR1-induced ISG expression and necroptotic cell death in IECs.

Conclusions:

• GCs exert distinct protective effects against endotoxemia through separate GR-dependent pathways.
• GCs suppress TNF production via GR monomers and inhibit TNF-induced cell death mediators via GR dimers.
• These findings deepen the understanding of TNF's role in endotoxemia and the multifaceted actions of GCs.