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Title

Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes

Authors
Berlier, C.
Published in Rheumatology. 2009, vol. 48, no. 3, p. 233-242
Abstract OBJECTIVES: We have recently shown that CRP induces chemokine secretion and adhesion molecule up-regulation in human primary monocytes cultured in adherence. Given the increasing evidence on direct immunomodulatory properties of statins, we investigated their possible anti-inflammatory role on CRP-treated human monocytes. METHODS: Monocytes were isolated by Ficoll-Percoll gradients and cultured in adherence to polystyrene. Chemokine secretion and adhesion molecule expression were detected by ELISA and flow cytometry. Migration assays were performed in modified Boyden chambers. Intracellular kinase activation was assessed by western blot. RESULTS: Treatment with simvastatin or atorvastatin decreased CRP-induced release of CCL2, CCL3 and CCL4. In addition, both statins reduced CRP-induced intercellular adhesion molecule (ICAM-1) up-regulation, but had no effects on CD11b and CD18. Treatments with 1 microM simvastatin or atorvastatin significantly inhibited monocyte migration in response to CRP. CD32 and CD64 (CRP receptors) expression on monocytes was not affected by statins. Statin-induced inhibition of CRP-mediated chemokine secretion, ICAM-1 up-regulation and migration occurred through the inhibition of extracellular signal-regulated kinase (ERK) 1/2. Treatment with L-mevalonate or farnesylpyrophosphate, but not geranylgeranyl-pyrophosphate reversed the statin-induced effect on CRP-mediated functions and ERK 1/2 phosphorylation, confirming that statins blocked CRP-induced ERK 1/2 phosphorylation through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. CONCLUSIONS: Statins inhibited CRP-induced chemokine secretion, ICAM-1 up-regulation and migration in human adherent monocytes, through the inhibition of HMG-CoA reductase-ERK 1/2 pathway. This pathway could represent a very promising target to reduce CRP-induced activities in monocyte-mediated diseases, such as atherosclerosis or RA.
Keywords C-Reactive Protein/*antagonists & inhibitors/pharmacologyCell Adhesion/physiologyCells, CulturedChemokines/*metabolismChemotaxis, Leukocyte/*drug effectsDose-Response Relationship, DrugEnzyme Activation/physiologyHumansHydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacologyIntercellular Adhesion Molecule-1/*biosynthesisMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3/metabolismMonocytes/drug effects/physiologyReceptors, Immunologic/drug effects/metabolismRecombinant Proteins/pharmacologyUp-Regulation/drug effects
Identifiers
PMID: 19151033
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Research groups Biologie du myocarde (22)
L'athérosclérose et ses complications cliniques (591)
Le rôle du système endocannabinoïde dans l'athérosclérose (882)
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MONTECUCCO, Fabrizio et al. Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes. In: Rheumatology, 2009, vol. 48, n° 3, p. 233-242. https://archive-ouverte.unige.ch/unige:19975

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Deposited on : 2012-04-23

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