AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

Diabetologia. 2010 Nov;53(11):2406-16. doi: 10.1007/s00125-010-1856-z. Epub 2010 Jul 24.


Aim/hypothesis: The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells.

Methods: IL-6-stimulated expression of the genes for acute-phase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazole-carboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists.

Results: AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3.

Conclusions/interpretation: We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Blotting, Western
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Interleukin-6 / pharmacology*
  • Liver / enzymology
  • Metformin / pharmacology
  • Phosphorylation / drug effects
  • RNA Interference
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleotides / pharmacology
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects


  • Hypoglycemic Agents
  • Interleukin-6
  • RNA, Small Interfering
  • Ribonucleotides
  • STAT3 Transcription Factor
  • Aminoimidazole Carboxamide
  • Metformin
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide