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Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells

A Peairs1, A Radjavi, S Davis

  • 1Virginia College of Osteopathic Medicine, Blacksburg, VA 24060, USA.

Clinical and Experimental Immunology
|May 15, 2009
PubMed

Insights

AMP-activated protein kinase (AMPK) activation by AICAR inhibits inflammatory mediator production in kidney cells. This suggests AICAR may be a therapeutic target for inflammatory diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) stimulate inflammatory mediator production.
  • MRL/lpr mice exhibit a heightened inflammatory response.
  • AMP-activated protein kinase (AMPK) activation by 5-amino-4-imidazole carboxamide riboside (AICAR) is known to inhibit certain inflammatory pathways.

Purpose of the Study:

  • To investigate the effect of AMPK activation on inflammatory mediator production in stimulated kidney mesangial cells from MRL/lpr mice.
  • To elucidate the signaling pathways involved in AICAR's anti-inflammatory effects in these cells.

Main Methods:

  • Primary kidney mesangial cells from MRL/lpr mice were cultured.
  • Cells were treated with AICAR and stimulated with LPS/IFN-gamma.
  • Levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, and interleukin-6 were measured.
  • Signaling pathways including PI3K/Akt and NF-kappaB were analyzed.
  • The role of adenosine kinase was assessed using 5'-iodotubercidin.

Main Results:

  • AICAR dose-dependently decreased iNOS, cyclooxygenase-2, and interleukin-6 production.
  • AICAR inhibited the LPS/IFN-gamma-stimulated PI3K/Akt signaling pathway.
  • AICAR did not affect LPS/IFN-gamma-mediated NF-kappaB phosphorylation or nuclear translocation.
  • Inhibition of adenosine kinase blocked AICAR's AMPK activation and anti-inflammatory effects.

Conclusions:

  • AMPK activation by AICAR inhibits inflammatory mediator production in kidney mesangial cells.
  • The mechanism involves the inhibition of the PI3K/Akt pathway via AMPK activation.
  • AICAR demonstrates potential as a therapeutic agent for inflammatory diseases.

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