title: Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction.
abstract: Metformin, a well known antidiabetic agent that improves peripheral insulin sensitivity, also elicits anti-inflammatory actions, but its mechanism is unclear. Here, we investigated the mechanism responsible for the anti-inflammatory effect of metformin action in lipopolysaccharide (LPS)-stimulated murine macrophages. Metformin inhibited LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF-3), a transcription factor and member of the cAMP-responsive element-binding protein family. ATF-3 knockdown abolished the inhibitory effects of metformin on LPS-induced proinflammatory cytokine production accompanied with reversal of metformin-induced suppression of mitogen-activated protein kinase (MAPK) phosphorylation. Conversely, AMP-activated protein kinase (AMPK) phosphorylation and NF-κB suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-κB enrichments on the promoters of IL-6 and TNF-α were replaced by ATF-3 upon metformin treatment. AMPK knockdown blunted all the effects of metformin (ATF-3 induction, proinflammatory cytokine inhibition, and MAPK inactivation), suggesting that AMPK activation by metformin is required for and precedes ATF-3 induction. Oral administration of metformin to either mice with LPS-induced endotoxemia or ob/ob mice lowered the plasma and tissue levels of TNF-α and IL-6 and increased ATF-3 expression in spleen and lungs. These results suggest that metformin exhibits anti-inflammatory action in macrophages at least in part via pathways involving AMPK activation and ATF-3 induction.
authors: Department of Pharmacology and Pharmaceutical Sciences and Gachon University, Incheon 406-799, Republic of Korea.
authors: Juyoung
authors: J
authors: Kim
authors: Department of Pharmacology and Pharmaceutical Sciences and Gachon University, Incheon 406-799, Republic of Korea.
authors: Hyun Jeong
authors: HJ
authors: Kwak
authors: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-799, Republic of Korea.
authors: Ji-Young
authors: JY
authors: Cha
authors: Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-799, Republic of Korea.
authors: Yun-Seung
authors: YS
authors: Jeong
authors: Bioorganic Science Division, Korea Research Institute of Chemical Technology, Taejeon, 305-343, Republic of Korea, and.
authors: Sang Dahl
authors: SD
authors: Rhee
authors: Bioorganic Science Division, Korea Research Institute of Chemical Technology, Taejeon, 305-343, Republic of Korea, and.
authors: Kwang Rok
authors: KR
authors: Kim
authors: Department of Pharmacology and Pharmaceutical Sciences and Gachon University, Incheon 406-799, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Incheon 405-760, Republic of Korea. Electronic address: hgcheon@gachon.ac.kr.
authors: Hyae Gyeong
authors: HG
authors: Cheon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D019446:Endotoxemia / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051700:Activating Transcription Factor 3; D000893:Anti-Inflammatory Agents; C103002:Atf3 protein, mouse; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D008687:Metformin; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases
keywords: ATF-3; Inflammation; Interleukin 6 (IL-6); Lipopolysaccharide (LPS); Macrophage; Metformin; Tumor Necrosis Factor (TNF)