AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages.
AICAR inhibits NFκB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages.
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DOI：
10.1038/s41598-018-26102-3
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发表时间：
2018-05-17
影响因子：
4.6
通讯作者：
Namgaladze D
中科院分区：
文献类型：
--
作者：
Kirchner J;Brüne B;Namgaladze D
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside(AICAR)是一种公认的AMPK的药理激活剂。据报道，AICAR和AMPK都有抗炎作用。然而，AICAR以许多AMPK非依赖性效应而闻名，尽管其机制仍不完全清楚。在这里，我们报道了AICAR对脂多糖诱导的原代人巨噬细胞炎症基因表达的有效抑制，这种抑制不依赖于其向AMPK激活的5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl单磷酸的转化。虽然AICAR不干扰脂多糖激活胞浆信号转导通路和核因子-核转录因子-核糖核酸酶B(NFRNA-κB，κB)的核转位，但它阻止了核转录因子κB和核糖核酸聚合酶II对靶基因启动子的募集。AICAR还抑制信号转导和转录激活子3(STAT3)依赖的IL-6和IL-10靶标的诱导，而不影响IL-4和二甲氧甘氨酸处理的巨噬细胞中依赖STAT6和HIF1α的基因表达。这指向了转录因子特有的作用模式。在体外的凝胶迁移率改变分析中，基因表达减弱与受损的NFκB和STAT3相关，但与HIF结合无关。结论：AICAR干扰核因子κB和STAT3DNA结合，调节炎症反应。
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.
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