Metformin Suppresses Lipopolysaccharide (LPS)-induced Inflammatory Response in Murine Macrophages via Activating Transcription Factor-3 (ATF-3) Induction

被引:170
|
作者
Kim, Juyoung [1 ]
Kwak, Hyun Jeong [1 ]
Cha, Ji-Young [2 ]
Jeong, Yun-Seung [2 ]
Rhee, Sang Dahl [3 ]
Kim, Kwang Rok [3 ]
Cheon, Hyae Gyeong [1 ,4 ]
机构
[1] Gachon Univ, Lee Gil Ya Canc & Diabet Inst, Dept Pharmacol & Pharmaceut Sci, Inchon 406799, South Korea
[2] Gachon Univ, Lee Gil Ya Canc & Diabet Inst, Dept Mol Med, Inchon 406799, South Korea
[3] Korea Res Inst Chem Technol, Bioorgan Sci Div, Taejon 305343, South Korea
[4] Gil Med Ctr, Gachon Med Res Inst, Inchon 405760, South Korea
基金
新加坡国家研究基金会;
关键词
NITRIC-OXIDE SYNTHASE; VASCULAR ENDOTHELIAL-CELLS; FACTOR-KAPPA-B; PROTEIN-KINASE; 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBOSIDE; NEGATIVE REGULATOR; DIABETES-MELLITUS; RESPIRATORY-CHAIN; GENE-EXPRESSION; MECHANISM;
D O I
10.1074/jbc.M114.577908
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-alpha (TNF-alpha) and interleukin- 6 (IL-6) in a concentration-dependent manner and in parallel induction of activating transcription factor-3 (ATF3), 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-kappa B suppression by metformin were unaffected by ATF-3 knockdown. ChIP-PCR analysis revealed that LPS-induced NF-kappa B enrichments on the promoters of IL-6 and TNF-alpha 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-alpha 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.
引用
收藏
页码:23246 / 23255
页数:10
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