Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages.
Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages.
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DOI：
10.1038/ni.2043
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发表时间：
2011-05-22
影响因子：
30.5
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中科院分区：
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内毒素耐受性是抑制过度炎性细胞因子产生和伴随的毒性的关键机制，其由巨噬细胞先前暴露于TLR配体诱导。尚未研究内源性细胞因子诱导耐受性。我们发现，以前暴露于TNF诱导巨噬细胞的耐受状态，减少细胞因子的产生LPS的挑战和保护LPS诱导的致死性。TNF诱导的耐受是通过两种抑制机制的协同作用介导的，即抑制LPS诱导的信号传导和染色质重塑。从机制上讲，TNF诱导的耐受性与TLR诱导的耐受性不同，因为它依赖于GSK 3，GSK 3通过增强A20和I-κBα的负反馈抑制染色质可及性并促进NF-κB信号的快速终止。这些结果揭示了TNF的意想不到的稳态功能，并提供了用于预防长期和过度炎症的GSK 3介导的机制。
Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production and attendant toxicity, is induced by prior exposure of macrophages to TLR ligands. Induction of tolerance by endogenous cytokines has not been investigated. We show that prior exposure to TNF induces a tolerant state in macrophages, with diminished cytokine production on LPS challenge and protection from LPS-induced lethality. TNF-induced tolerization was mediated by coordinate action of two inhibitory mechanisms, suppression of LPS-induced signaling and chromatin remodeling. Mechanistically, TNF-induced tolerance was distinct from TLR-induced tolerance as it was dependent on GSK3, which suppressed chromatin accessibility and promoted rapid termination of NF-κB signaling by augmenting negative feedback by A20 and I-κBα. These results reveal an unexpected homeostatic function of TNF and provide a GSK3-mediated mechanism for preventing prolonged and excessive inflammation.