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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway
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α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

机译：α-硫辛酸通过激活磷酸肌醇3激酶/ Akt信号通路减弱LPS诱导的炎症反应

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摘要

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was recently shown to negatively regulate LPS-induced acute inflammatory responses. We previously observed that the metabolic thiol antioxidant α-lipoic acid (LA) inhibits LPS-induced expression of cellular adhesion molecules and adherence of monocytes to human aortic endothelial cells. Here we investigated the mechanism by which LA attenuates LPS-induced monocyte activation in vitro and acute inflammatory responses in vivo. Incubation of human monocytic THP-1 cells with LA induced phosphorylation of Akt in a time- and dose-dependent manner. In cells pretreated with LA followed by LPS, Akt phosphorylation was elevated initially and further increased during incubation with LPS. This LA-dependent increase in Akt phosphorylation was accompanied by inhibition of LPS-induced NF-κB DNA binding activity and up-regulation of TNFα and monocyte chemoattractant protein 1. Lipoic acid-dependent Akt phosphorylation and inhibition of NF-κB activity were abolished by the PI3K inhibitors LY294002 and wort-mannin. Furthermore, LA treatment of LPS-exposed C57BL/6N mice strongly enhanced phosphorylation of Akt and glycogen synthase kinase 3β in blood cells; inhibited the LPS-induced increase in serum concentrations and/or tissue expression of adhesion molecules, monocyte chemoattractant protein 1, and TNFα; and attenuated NF-κB activation in lung, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflam-matory effects of LA were abolished by treatment of the animals with wortmannin. We conclude that LA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo by activating the PI3K/Akt pathway. Lipoic acid may be useful in the prevention of sepsis and inflammatory vascular diseases.
机译：最近显示磷酸肌醇3-激酶（PI3K）/蛋白激酶B（Akt）信号通路负调控LPS诱导的急性炎症反应。我们以前观察到代谢硫醇抗氧化剂α-硫辛酸（LA）抑制LPS诱导的细胞粘附分子表达和单核细胞与人主动脉内皮细胞的粘附。在这里，我们研究了LA减弱体外LPS诱导的单核细胞激活和体内急性炎症反应的机制。用LA孵育人单核THP-1细胞以时间和剂量依赖性方式诱导Akt磷酸化。在先用LA预处理再用LPS预处理的细胞中，Akt磷酸化水平先升高，再与LPS一起孵育。 LA依赖性的Akt磷酸化增加伴随着LPS诱导的NF-κBDNA结合活性的抑制以及TNFα和单核细胞趋化蛋白1的上调。 PI3K抑制剂LY294002和麦芽汁甘露醇。此外，LA处理暴露于LPS的C57BL / 6N小鼠可显着增强血细胞中Akt和糖原合酶激酶3β的磷酸化。抑制LPS诱导的血清浓度和/或粘附分子，单核细胞趋化蛋白1和TNFα的组织表达增加；并减弱肺，心脏和主动脉中的NF-κB活化。硫辛酸还可以改善内毒素血症小鼠的存活率。通过用渥曼青霉素处理动物，可以消除洛杉矶的所有这些抗炎作用。我们得出结论，LA通过激活PI3K / Akt途径在体外和体内抑制LPS诱导的单核细胞激活和急性炎症反应。硫辛酸可用于预防败血症和炎性血管疾病。

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