@Article{ecn.2009.0162,
AUTHOR = {Benoit Massonnet, Sylvain Normand, Reinhard Moschitz, Adriana Delwail, Laure Favot, Martine Garcia, Nicolas Bourmeyster, Laurence Cuisset, Gilles Grateau, Franck Morel, Christine Silvain, Jean-Claude Lecron},
TITLE = {Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes},
JOURNAL = {European Cytokine Network},
VOLUME = {20},
YEAR = {2009},
NUMBER = {3},
PAGES = {112--120},
URL = {http://www.techscience.com/ECN/v20n3/65896},
ISSN = {1952-4005},
ABSTRACT = {Objective. The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors)
on the inflammatory response remain unclear. HMGR is implicated in the mevalonate path-way,
directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine pro-duction
by peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The aim was to identify a specific
cytokine “signature” of cells under simvastatin treatment in order to link pharmacological inhibition of the
mevalonate pathway and inflammation. Methods. Normal human PBMCs and THP-1 cells were cultured with
inhibitors of HMGR (simvastatin), geranylgeranyltransferase (GGTI-298), farnesyltransferase (FTI-277), and/or
caspase-1 (Z-VAD(Ome)-FMK). Following culture, cytokine production, caspase-1 activity, IL-1β mRNA and
Rac-1 activity were determined. Results. Pharmacological inhibition of the mevalonate pathway specifically
enhanced the release of IL-1α, IL-1β and IL-18 and inhibited IL-1ra production by LPS-activated PBMCs and
THP-1 cells. Simvastatin did not modify pro-IL-1β expression, but enhanced caspase-1 activity, the enzyme
responsible for IL-1β and IL-18 maturation. GGTI-298 also enhanced IL-1-family cytokine production, showing
that geranylgeranylation is involved in caspase-1 activation. Additionally, simvastatin enhanced Rac-1 activity.
Conclusion. Pharmacological inhibition of the mevalonate pathway by statins highlighted the specific induction
of the proinflammatory cytokines of the IL-1 family whose maturation is either directly (i.e. IL-1β and IL-18),
or indirectly (i.e. IL-1α) dependant on caspase-1.},
DOI = {10.1684/ecn.2009.0162}
}