Metformin Inhibits the Production of Reactive Oxygen Species from NADH:ubiquinone Oxidoreductase to Limit Induction of IL-1{beta}, and Boosts IL-10 in LPS-activated Macrophages [Metabolism]

July 7th, 2015 by Kelly, B., Tannahill, G. M., Murphy, M. P., O'Neill, L. A. J.

Metformin, a frontline treatment for Type II Diabetes Mellitus (T2DM)3, decreases production of the pro-form of the inflammatory cytokine interleukin (IL)-1β in response to lipopolysaccharide (LPS) in macrophages. We have found that it specifically inhibited pro-IL-1β production, having no effect on tumour necrosis factor-α (TNF-α). Furthermore, metformin boosted induction of the anti-inflammatory cytokine IL-10 in response to LPS. We ruled out a role for AMP-activated protein kinase (AMPK) in the effect of metformin, since activation of AMPK with A769662 did not mimic metformin here. Furthermore, metformin was still inhibitory in AMKPα1- or AMPKβ1-deficient cells. The activity of NADH:ubiquinone oxidoreductase (complex I) was inhibited by metformin. Another complex I inhibitor, rotenone, mimicked the effect of metformin on pro-IL-1β and IL-10. LPS induced reactive oxygen species (ROS) production, an effect inhibited by metformin or rotenone pretreatment. MitoQ, a mitochondria-targeted antioxidant, decreased LPS-induced IL-1β without affecting TNF-α. These results therefore implicate complex I in LPS action in macrophages.
  • Posted in Journal of Biological Chemistry, Publications
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