Abstract
Interleukin-6 (IL-6) induces inflammatory signalling in liver, leading to impaired insulin action in hepatocytes. In this study, we demonstrate that pharmacological activation of AMP-activated protein kinase (AMPK) represses IL-6-stimulated expression of proinflammatory markers serum amyloid A (Saa) as well as suppressor of cytokine signalling 3 (Socs3) in mouse liver. Further studies using the human hepatocellular carcinoma cell line HepG2 suggest that AMPK inhibits IL-6 signalling by repressing IL-6-stimulated phosphorylation of several downstream components of the pathway such as Janus kinase 1 (JAK1), SH2-domain containing protein tyrosine phosphatase 2 (SHP2) and signal transducer and activator of transcription 3 (STAT3). In summary, inhibition of IL-6 signalling cascade in liver by the metabolic master switch of the body, AMPK, supports the role of this kinase as a crucial point of convergence of metabolic and inflammatory pathways in hepatocytes.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylate Kinase / metabolism*
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Aminoimidazole Carboxamide / analogs & derivatives*
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Aminoimidazole Carboxamide / pharmacology
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Enzyme Activation / drug effects
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Enzyme Activators / pharmacology*
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Gene Expression
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Gene Expression Regulation / immunology
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Hep G2 Cells
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Hepatocytes / drug effects
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Hepatocytes / enzymology*
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Hepatocytes / immunology
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Humans
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Interleukin-6 / physiology*
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Liver / drug effects
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Liver / enzymology
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Liver / pathology
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Male
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Metformin / pharmacology
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Mice
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Mice, Inbred C57BL
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Phosphorylation
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Protein Processing, Post-Translational
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Ribonucleotides / pharmacology*
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STAT3 Transcription Factor / metabolism
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Serum Amyloid A Protein / genetics
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Serum Amyloid A Protein / metabolism
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
Substances
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Anti-Inflammatory Agents
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Enzyme Activators
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IL6 protein, human
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Interleukin-6
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Ribonucleotides
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STAT3 Transcription Factor
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Saa2 protein, mouse
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Serum Amyloid A Protein
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Aminoimidazole Carboxamide
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Metformin
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Adenylate Kinase
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AICA ribonucleotide