Pharmacological inhibitors of the mevalonate pathway activate pro-IL-1 processing and IL-1 release by human monocytes.
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 pathway, directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine production 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-1beta mRNA and Rac-1 activity were determined.


RESULTS
Pharmacological inhibition of the mevalonate pathway specifically enhanced the release of IL-1alpha, IL-1beta and IL-18 and inhibited IL-1ra production by LPS-activated PBMCs and THP-1 cells. Simvastatin did not modify pro-IL-1beta expression, but enhanced caspase-1 activity, the enzyme responsible for IL-1beta 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.


CONCLUSIONS
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-1beta and IL-18), or indirectly (i.e. IL-1alpha) dependant on caspase-1.
Massonnet
Benoit
B
Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, Poitiers, France.
Normand
Sylvain
S
Moschitz
Reinhard
R
Delwail
Adriana
A
Favot
Laure
L
Garcia
Martine
M
Bourmeyster
Nicolas
N
Cuisset
Laurence
L
Grateau
Gilles
G
Morel
Franck
F
Silvain
Christine
C
Lecron
Jean-Claude
JC
D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011498:Protein Precursors; D006160:Guanosine Triphosphate; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1; D020830:rac1 GTP-Binding Protein; D008798:Mevalonic Acid