Open Access

ARTICLE

Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes

Benoit Massonnet^1,6,*, Sylvain Normand^1,*, Reinhard Moschitz¹, Adriana Delwail¹, Laure Favot¹, Martine Garcia¹, Nicolas Bourmeyster², Laurence Cuisset³, Gilles Grateau⁴, Franck Morel¹, Christine Silvain^1,5, Jean-Claude Lecron^1,6

1 Laboratoire Inflammation, tissus épithéliaux et cytokines; EA 4331, Université de Poitiers; France
2 Laboratoire de Génétique moléculaire de l’adressage et de la signalisation, CNRS UMR 6187, Poitiers, France
3 Department of Biochemical Genetics, Pavillon Cassini, CHU and Institut Cochin, Université Paris 5, Paris, France
4 Service de médecine interne, Hôpital Tenon; Université Paris 6, Paris, France
5 Service d’hépato-gastroentérologie, CHU de Poitiers, France
6 Service immunologie-inflammation, CHU de Poitiers, France

* Corresponding Author: J.-C. Lecron,

European Cytokine Network 2009, 20(3), 112-120. https://doi.org/10.1684/ecn.2009.0162

Accepted 19 August 2009;

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.

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