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

• Published in: The Journal of biological chemistry 2014-08, Vol.289 (33), p.23246-23255
• Main Authors: Kim, Juyoung, Kwak, Hyun Jeong, Cha, Ji-Young, Jeong, Yun-Seung, Rhee, Sang Dahl, Kim, Kwang Rok, Cheon, Hyae Gyeong
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 3 - genetics; Activating Transcription Factor 3 - metabolism; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Cell Line; Endotoxemia - blood; Endotoxemia - genetics; Endotoxemia - metabolism; Endotoxemia - pathology; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Knockdown Techniques; Hypoglycemic Agents - pharmacology; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - pathology; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Lipopolysaccharides - toxicity; Macrophages - metabolism; Macrophages - pathology; Male; Metformin - pharmacology; Mice; Mice, Obese; Phosphorylation - drug effects; Phosphorylation - genetics; Signal Transduction; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.577908

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.