TitleAlpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway.
Publication TypeJournal Article
Year of Publication2007
AuthorsZhang W-J, Wei H, Hagen T, Frei B
JournalProc Natl Acad Sci U S A
Date Published2007 Mar 06
KeywordsAnimals, Anti-Inflammatory Agents, Antioxidants, Cell Line, Tumor, Humans, Inflammation, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Sepsis, Signal Transduction, Thioctic Acid

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID17360480
PubMed Central IDPMC1805485
Grant ListP01 AT002034 / AT / NCCIH NIH HHS / United States
ES 11542 / ES / NIEHS NIH HHS / United States
P01 AT 002034 / AT / NCCIH NIH HHS / United States