LPS inhibits caspase 3-dependent apoptosis in RAW264.7 macrophages induced by the AMPK activator AICAR

Biochem Biophys Res Commun. 2014 May 9;447(3):520-5. doi: 10.1016/j.bbrc.2014.04.008. Epub 2014 Apr 13.

Abstract

AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have a therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.

Keywords: AICAR; AMPK; Apoptosis; Caspase 3; LPS; Macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / metabolism
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Caspase 3 / metabolism*
  • Cell Line
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Lipopolysaccharides / immunology*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Metformin / pharmacology
  • Mice
  • Ribonucleotides / metabolism*
  • Ribonucleotides / pharmacology
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Lipopolysaccharides
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Metformin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • AMP-Activated Protein Kinases
  • Caspase 3
  • AICA ribonucleotide