title: 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.
abstract: 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.
authors.affiliation: From the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and.
authors.forename: Beth
authors.initials: B
authors.lastname: Kelly
authors.affiliation: From the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tannahill
authors.affiliation: the MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: From the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and kellyb3@tcd.ie.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D012402:Rotenone; D016753:Interleukin-10; D008687:Metformin; D000263:Adenylate Kinase; D042967:Electron Transport Complex I
keywords: AMP-activated kinase (AMPK); IL-1; LPS; complex I; metformin