title: Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro.
abstract: Metformin, an antidiabetic agent, has been shown to reduce atherothrombotic disease in diabetic patients independent of antihyperglycemic effect. Recent studies have demonstrated that metformin attenuates the proinflammatory responses in human vascular wall cells and macrophages. However, the detailed molecular mechanisms underlying these therapeutic effects remain unclear. In the present study, we investigated the effects of metformin on tumor necrosis factor (TNF) production and tissue factor (TF) expression in isolated human monocytes stimulated with lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL). Metformin significantly inhibited both TNF production and TF expression in isolated human monocytes stimulated with LPS or oxLDL. Metformin also significantly inhibited TNF and TF mRNA in human monocytes stimulated with LPS. Although metformin did not inhibit the activation of either nuclear factor-kappaB or activator protein-1, it inhibited the expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 in monocytes stimulated with LPS or oxLDL. These results suggest that metformin may attenuate the inflammatory responses, at least in part, by suppressing the production of both TNF and TF through the inhibition of the ERK1/2-Egr-1 pathway in human monocytes.
authors.affiliation: Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya City, Japan.
authors.forename: Masatoku
authors.initials: M
authors.lastname: Arai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Uchiba
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Komura
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mizuochi
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D051766:Early Growth Response Protein 1; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; D008687:Metformin; D048049:Extracellular Signal-Regulated MAP Kinases