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Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes

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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.

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Abbreviations

A:

Annexin V

ALD:

Alendronate

FOH:

Farnesol

GGOH:

Geranylgeraniol

GOH:

Geraniol

IL-1β:

Interleukin-1beta

IL-1RA:

IL-1β receptor antagonist

LIM:

Limonene

LPS:

Lipopolysaccharide

ManA:

Manumycin A

MKD:

Mevalonate kinase deficiency

MOH:

Menthol

PCD:

Programmed cell death

PI:

Propidium iodide

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Acknowledgments

The authors are grateful to Dr. A. Tommasini (Paediatric Division, IRCCS “Burlo Garofolo”) for providing Kineret®. This work was supported by a grant from the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” (RC 13/08). SC is recipient of a fellowship grant from European Project “Talents for an International House” within the framework of the 7th Research & Development Framework Programme PEOPLE—Marie Curie Actions—COFUND (Co-Funding of Regional National and International Programmes).

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Authors and Affiliations

  1. Medical Genetic Service, Institute for Maternal and Child Health “Burlo Garofolo”, Via dell’Istria, 65/1, 34137, Trieste, Italy

    Annalisa Marcuzzi, Martina Girardelli, Sergio Crovella & Alessandra Pontillo

  2. Department of Reproductive and Developmental Sciences and Public Health Care, University of Trieste, 34137, Trieste, Italy

    Elisa Piscianz

  3. Department of Genetics, Federal University of Pernambuco, Av. Academico H Ramos, Cidade Universitaria, 50, 740-530, Recife, Brazil

    Sergio Crovella

Authors
  1. Annalisa Marcuzzi
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  2. Elisa Piscianz
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  3. Martina Girardelli
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  4. Sergio Crovella
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  5. Alessandra Pontillo
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Correspondence to Annalisa Marcuzzi.

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Marcuzzi, A., Piscianz, E., Girardelli, M. et al. Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes. Apoptosis 16, 882–888 (2011). https://doi.org/10.1007/s10495-011-0621-1

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  • DOI: https://doi.org/10.1007/s10495-011-0621-1

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