Visit our Expo - Redox and Inflammation signaling 2012

Acute anti-inflammatory properties of statins involve Peroxisome Proliferator-Activated
Receptor-alpha via inhibition of the PKC signalling pathway
Réjane Paumelle 1 , Christophe Blanquart 1 , Olivier Briand 1 , Olivier Barbier 1 , Gaëtane
Woerly 2 Christian Duhem 1 , Frédéric Percevault 1 , Jean-Charles Fruchart 1 , David
Dombrowicz 2 , Corine Glineur 1 and Bart Staels 1,3 .
1 Département d’Athérosclerose, U545 Inserm, Institut Pasteur de Lille and Faculté de
Pharmacie, Université de Lille II, Lille, France. 2 Inserm U547, Institut Pasteur de Lille,
Lille, France. E-mail: Bart.Staels@pasteur-lille.fr
Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase used in the
prevention of cardiovascular diseases (CVD). In addition to their cholesterol-lowering
activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their
beneficial effects not only on CVD, but also on lipid-unrelated immune and inflammatory
diseases, such as rheumatoid arthritis, asthma, stroke and transplant rejection. However, the
molecular mechanisms involved in these anti-inflammatory properties of statins are
unresolved. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)-alpha
that is expressed in inflammation regulatory cell types, such as macrophages, exerts potent
anti-inflammatory activities. In this study we present genetic evidence for a role for this
nuclear receptor in mediating the lipid-independent anti-inflammatory activities of statins in
two in vivo models of acute inflammation. Furthermore, the inhibitory effects of statins on
lipopolysaccharide (LPS)-induced inflammatory response genes were abolished in PPARalpha-deficient
macrophages and neutrophils, two cell types involved in acute inflammatory
responses. Moreover, we provide a molecular mechanism explaining these observations by
showing that simvastatin inhibited PPAR-alpha phosphorylation by LPS-activated PKCalpha.
A constitutive active form of PKC-alpha inhibited NF-kappaB transrepression by
PPAR-alpha whereas simvastatin enhanced transrepression activity of wild-type PPAR-alpha,
but not of PPAR-alpha mutated in its PKC phosphorylation sites. These data indicate that the
acute anti-inflammatory effect of simvastatin occurs via PPAR-alpha by a mechanism
involving inhibition of PKC-alpha inactivation of PPAR-alpha transrepression activity.
PUBLICATIONS
- Tulasne, D., Paumelle, R., Weidner, M., Vandenbunder, B. and Fafeur, V. The
multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS
signaling and cell scattering. 1999. Mol. Biol. Cell. 10, 551-565.
- Paumelle, R., Tulasne, D., Leroy, C., Coll, J., Vandenbunder, B. and Fafeur, V. Sequential
activation of ERK and repression of JNK by SF/HGF in MDCK epithelial cells. 2000. Mol.
Biol. Cell. 11, 3751-3763.
- Paumelle, R., Tulasne, D., Kherrouche, Z., Plaza, S., Leroy, C., Reveneau, S.,
Vandenbunder, B. And Fafeur, V. Hepatocyte growth factor/scatter factor activates the ETS1
transcription factor by a RAS-RAF-MEK-ERK signaling pathway. 2002. Oncogene. 21:
2309-2319.
- Blanquart, C., Mansouri, R., Paumelle, R., Fruchart, J. C., Staels, B. The protein kinase C
signalling pathway regulates a molecular switch between transactivation and transrepression
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