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.

中文翻译：

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糖皮质激素通过双重控制系统限制脂多糖诱导的致死性炎症。

脂多糖（LPS）可以导致致命的内毒素血症，这是一种系统性炎症反应综合征（SIRS），其特征在于细胞因子如TNF的系统释放。作为革兰氏阴性菌感染的模型系统，对内毒素血症进行了深入研究。LPS和TNF诱导的SIRS强烈诱导干扰素刺激的基因（ISG），其中一些会导致肠上皮细胞（IEC）的细胞死亡。众所周知，糖皮质激素（GC s）可防止内毒素血症。通过应用大量的突变小鼠系，我们的数据支持了一个模型，GC通过该模型通过其糖皮质激素受体（GR）运用两种关键机制来控制内毒素血症，（i）在GR单体中以GR单体依赖性方式抑制TNF产生的水平，以及（ii）在GR二聚体中以IEC s抑制TNFR 1诱导的ISG基因表达和坏死性细胞死亡介质的水平。依赖方式。我们的数据为了解TNF在内毒素血症中的作用以及GC在抑制TNF产生和活性中的两个独立关键作用方面提供了新的重要见解。