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.

TitleMetformin 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.
Publication TypeJournal Article
Year of Publication2015
AuthorsKelly, B, Tannahill, GM, Murphy, MP, O'Neill, LAJ
JournalJ Biol Chem
Volume290
Issue33
Pagination20348-59
Date Published2015 Aug 14
ISSN1083-351X
KeywordsAdenylate Kinase, Animals, Electron Transport Complex I, Interleukin-10, Interleukin-1beta, Lipopolysaccharides, Macrophage Activation, Macrophages, Metformin, Mice, Mice, Inbred C57BL, Reactive Oxygen Species, Rotenone
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.

DOI10.1074/jbc.M115.662114
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M115.662114
PubMed ID26152715
PubMed Central IDPMC4536441
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom