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首页> 外文期刊>Nature immunology >Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages.
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Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages.

机译：肿瘤坏死因子诱导巨噬细胞内毒素对GSK3激酶介导的交叉耐受。

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摘要

Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production, is induced by prior exposure of macrophages to Toll-like receptor (TLR) ligands. Induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Here we show that prior exposure to tumor necrosis factor (TNF) induced a tolerant state in macrophages, with less cytokine production after challenge with lipopolysaccharide (LPS) and protection from LPS-induced death. TNF-induced cross-tolerization was mediated by suppression of LPS-induced signaling and chromatin remodeling. TNF-induced cross-tolerance was dependent on the kinase GSK3, which suppressed chromatin accessibility and promoted rapid termination of signaling via the transcription factor NF-kappaB by augmenting negative feedback by the signaling inhibitors A20 and IkappaBalpha. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation.
机译：内毒素耐受是抑制巨噬细胞过度炎性细胞因子产生的关键机制，它是由巨噬细胞事先暴露于Toll样受体（TLR）配体引起的。尚未研究内源性细胞因子对内毒素的交叉耐受性的诱导。在这里，我们显示，先前暴露于肿瘤坏死因子（TNF）会诱导巨噬细胞产生耐受状态，用脂多糖（LPS）攻击后细胞因子的产生会减少，并防止LPS诱导的死亡。 TNF诱导的交叉耐受是由LPS诱导的信号传导和染色质重塑的抑制介导的。 TNF诱导的交叉耐受性取决于激酶GSK3，该激酶抑制染色质可及性并通过增加信号抑制剂A20和IkappaBalpha的负反馈来促进通过转录因子NF-κB的信号快速终止。我们的结果证明了TNF具有出乎意料的稳态功能，以及GSK3介导的机制可防止长时间和过度的炎症。

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