Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages

• Published in: The Journal of biological chemistry 2015-08, Vol.290 (33), p.20348-20359
• Main Authors: Kelly, Beth, Tannahill, Gillian M., Murphy, Michael P., O'Neill, Luke A.J.
• Format: Article
• Language: English
• Subjects: Adenylate Kinase - genetics; Adenylate Kinase - metabolism; AMP-activated kinase (AMPK); Animals; complex I; Electron Transport Complex I - metabolism; IL-1; Immunology; Interleukin-10 - biosynthesis; Interleukin-1beta - biosynthesis; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; LPS; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - metabolism; metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Reactive Oxygen Species - metabolism; Rotenone - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.662114

Metformin, a frontline treatment for type II diabetes mellitus, decreases production of the pro-form of the inflammatory cytokine IL-1β in response to LPS in macrophages. We found that it specifically inhibited pro-IL-1β production, having no effect on 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 because 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 production, an effect inhibited by metformin or rotenone pretreatment. MitoQ, a mitochondrially targeted antioxidant, decreased LPS-induced IL-1β without affecting TNF-α. These results, therefore, implicate complex I in LPS action in macrophages. Background: The antidiabetic drug and mitochondrial NADH:ubiquinone oxidoreductase (complex I) inhibitor metformin has anti-inflammatory activity. Results: Complex I inhibition decreases LPS-induced IL-1β and boosts IL-10. Mitochondrial ROS may be a signal driving LPS-induced IL-1β. Conclusion: Complex I has a role in the induction of cytokines by LPS. Significance: This study provides insight into the anti-inflammatory action of metformin and reveals a role for complex I dysfunction in inflammatory signaling.