Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes.

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.

• Authors: Annalisa Marcuzzi, Elisa Piscianz, Martina Girardelli, Sergio Crovella, Alessandra Pontillo
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 16 Issue 9 Pg. 882-8 (Sep 2011) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 21667041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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