Figure 7. Graphical abstract.

In the intestinal epithelial cells (IECs) of the small intestine, a constitutive expression of interferon‐stimulated genes (ISGs) is suppressed by the presence of dimer GR. During LPS‐induced endotoxemia, LPS has indirect effects on the IECs: TLR4 binding on macrophages results in production of diverse cytokines, such as IFNs, IL‐1β, and TNF. TNF performs its effects on IECs via binding to TNFR1. TNF induces the expression of ISGs, such as necroptosis mediators: Mlkl, Zbp1 and Ripk3. High expression of these mediators can potentially lead to cell death of the IEC and eventually lethality of the animal. When no (dimer) GR is present in the IECs, there is no dampening of the constitutive ISGs signature. We hypothesize that necroptosis proteins such as MLKL and ZBP1 are in this case “ready to use” and that TNFR1 signaling by TNF can directly lead to necroptosis, death of the cell and eventually lethality. This hypothesis still needs further investigation.