Zhang Wei-Jian, Wei Hao, Hagen Tory, Frei Balz
Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512.
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4077-82. doi: 10.1073/pnas.0700305104. Epub 2007 Feb 27.
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 alpha-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-kappaB DNA binding activity and up-regulation of TNFalpha and monocyte chemoattractant protein 1. Lipoic acid-dependent Akt phosphorylation and inhibition of NF-kappaB activity were abolished by the PI3K inhibitors LY294002 and wortmannin. Furthermore, LA treatment of LPS-exposed C57BL/6N mice strongly enhanced phosphorylation of Akt and glycogen synthase kinase 3beta in blood cells; inhibited the LPS-induced increase in serum concentrations and/or tissue expression of adhesion molecules, monocyte chemoattractant protein 1, and TNFalpha; and attenuated NF-kappaB activation in lung, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflammatory 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.
磷酸肌醇3激酶（PI3K）/蛋白激酶B（Akt）信号通路最近被证明对脂多糖（LPS）诱导的急性炎症反应起负调控作用。我们之前观察到代谢性硫醇抗氧化剂α-硫辛酸（LA）可抑制LPS诱导的细胞黏附分子表达以及单核细胞与人主动脉内皮细胞的黏附。在此，我们研究了LA在体外减弱LPS诱导的单核细胞活化以及在体内减轻急性炎症反应的机制。用LA孵育人单核细胞THP-1细胞可诱导Akt磷酸化，且呈时间和剂量依赖性。在用LA预处理后再给予LPS的细胞中，Akt磷酸化最初升高，并在与LPS孵育期间进一步增加。这种LA依赖的Akt磷酸化增加伴随着LPS诱导的核因子κB（NF-κB）DNA结合活性的抑制以及肿瘤坏死因子α（TNFα）和单核细胞趋化蛋白1的上调。PI3K抑制剂LY294002和渥曼青霉素可消除硫辛酸依赖的Akt磷酸化及NF-κB活性的抑制。此外，用LA处理暴露于LPS的C57BL/6N小鼠可强烈增强血细胞中Akt和糖原合酶激酶3β的磷酸化；抑制LPS诱导的血清浓度和/或组织中黏附分子、单核细胞趋化蛋白1和TNFα表达的增加；并减弱肺、心脏和主动脉中的NF-κB活化。硫辛酸还可提高内毒素血症小鼠的存活率。用渥曼青霉素处理动物可消除LA的所有这些抗炎作用。我们得出结论，LA通过激活PI3K/Akt通路在体外和体内抑制LPS诱导的单核细胞活化和急性炎症反应。硫辛酸可能有助于预防败血症和炎症性血管疾病。
