title: 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.affiliation: Medical Genetic Service, Institute for Maternal and Child Health "Burlo Garofolo", Trieste, Italy. marcuzzi@burlo.trieste.it
authors.forename: Annalisa
authors.initials: A
authors.lastname: Marcuzzi
authors.forename: Elisa
authors.initials: E
authors.lastname: Piscianz
authors.forename: Martina
authors.initials: M
authors.lastname: Girardelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pontillo
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015415:Biomarkers; D053898:Biosynthetic Pathways; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3 / Q000276:immunology; D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009336:Necrosis / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D013729:Terpenes / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009842:Oligopeptides; D013729:Terpenes; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020170:Caspase 1; D008798:Mevalonic Acid; D019386:Alendronate