Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation

Nan-Lan Huang, Shu-Hui Chiang, Chia-Hsiang Hsueh, Yao-Jen Liang, Yi-Jung Chen, Ling-Ping Lai
International Journal of Cardiology 2009 May 15, 134 (2): 169-75

BACKGROUND: Metformin has been reported to reduce cardiovascular complications in diabetic patients. The purpose of the present study was to investigate the anti-inflammatory effects of metformin on endothelial cells and the related molecular mechanisms.

METHODS: Human umbilical vein endothelial cells (HUVEC) were used for the experiments. The effects of metformin on TNF-alpha-induced IL-6 production were investigated. Modulation of AMPK and related signal transduction pathways were also performed.

RESULTS: TNF-alpha increased IL-6 secretion by HUVEC in a dose-dependent manner but inhibitors of NF-kappaB abolished the TNF-alpha-induced IL-6 production. Pre-treatment with metformin (100-1000 micromol/L) also inhibited TNF-alpha-induced IL-6 production, phosphorylation of IkappaB kinase (IKK) alpha/beta and IkappaB-alpha degradation. Metformin increased phosphorylation of AMP-activated kinase (AMPK) but wortmannin, a PI3K inhibitor, negated its effects on AMPK phosphorylation and TNF-alpha-induced IkappaB-alpha degradation. AICAR, a direct AMPK activator, had inhibitory effects on TNF-alpha-induced IL-6 production, similar to that of metformin. Transfection of siRNA against alpha1-AMPK eradicated the inhibitory effects of metformin on TNF-alpha-induced IL-6, implying the essential role of AMPK.

CONCLUSIONS: Metformin had anti-inflammatory effects on endothelial cells and inhibited TNF-alpha-induced IKKalpha/beta phosphorylation, IkappaB-alpha degradation and IL-6 production in HUVEC. This effect was related to PI3K-dependent AMPK phosphorylation.

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