Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes

Apoptosis. 2011 Sep;16(9):882-8. doi: 10.1007/s10495-011-0621-1.

Abstract

The inhibition of mevalonate pathway by the aminobisphosphonate alendronate (ALD) has been previously associated with an augmented lipopolysaccharide-induced interleukin-1beta (IL-1β) secretion in monocytes, as demonstrated in an auto-inflammatory disease known as mevalonate kinase deficiency (MKD). In this study we investigated the effect of ALD + LPS on monocyte cell line (Raw 264.7) death. ALD strongly augmented LPS-induced programmed cell death (PCD) as well as IL-1β secretion in Raw murine monocytes, whereas necrosis was rather unaffected. ALD + LPS induced caspase-3 activation. Inhibition of IL-1β stimulation partially restored cell viability. These findings suggest that the inhibition of mevalonate pathway, together with a bacterial stimulus, induce a PCD partly sustained by the caspase-3-related apoptosis and partly by caspase-1-associated pyroptosis. The involvement of pyroptosis is a novel hit in our cell model and opens discussions about its role in inflammatory cells with chemical or genetic inhibition of mevalonate pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alendronate / pharmacology
  • Animals
  • Apoptosis / immunology*
  • Biomarkers
  • Biosynthetic Pathways
  • Caspase 1 / immunology
  • Caspase 1 / metabolism
  • Caspase 3 / immunology
  • Caspase Inhibitors
  • Cell Line
  • Cell Survival
  • Enzyme Activation
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Mevalonic Acid / metabolism*
  • Mice
  • Monocytes / drug effects*
  • Monocytes / immunology
  • Necrosis / immunology
  • Necrosis / metabolism
  • Oligopeptides / pharmacology
  • Terpenes / immunology
  • Terpenes / metabolism

Substances

  • Biomarkers
  • Caspase Inhibitors
  • Interleukin-1beta
  • Lipopolysaccharides
  • Oligopeptides
  • Terpenes
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • Casp3 protein, mouse
  • Caspase 3
  • Caspase 1
  • Mevalonic Acid
  • Alendronate