OBJECTIVE: HMG-CoA reductase inhibitors (statins) possess anti-inflammatory and 
immunomodulatory properties that are independent of their lipid-lowering action. 
As the CD40-CD40L signaling pathway is implicated in the modulation of 
inflammatory responses between vascular cells, involving adhesion molecules, 
pro-inflammatory cytokines, chemokines, we sought to investigate the potential 
role of statins in regulating the expression of CD40.
METHODS AND RESULTS: Using Western blot, flow cytometry and immunohistochemistry 
analyses, we observed that four different statins reduced IFN-gamma-induced CD40 
expression in human vascular cells (endothelial cells, smooth muscle cells, 
macrophages and fibroblasts). This effect was dose-dependent (from 5 microM to 
80 nM) and reversed by addition of L-mevalonate. Activation of vascular cells by 
human recombinant CD40L, as measured by ELISA for IL-6, IL-8 and MCP-1, was 
strongly reduced when cells were treated with statins. Immunostaining of human 
carotid atherosclerotic lesions of patients subjected to statin treatment 
revealed less CD40 expression on a 'per vascular cell' basis compared to control 
patients. Although many pleiotropic effects of statins are mediated by nitric 
oxide synthase (NOS)- or peroxisome proliferator-activated receptor 
(PPAR)-dependent signaling pathways, we observed similar statin-induced 
reduction of CD40 expression using NOS inhibitors or different PPAR ligands.
CONCLUSION: Statins decrease CD40 expression and CD40-related activation of 
vascular cells. These effects are partially reversed by the HMG-CoA reductase 
product L-mevalonate and are mediated by NOS- or PPAR-dependent pathways. 
Altogether, these findings provide mechanistic insight into the beneficial 
effects of statins on atherogenesis. They also provide a scientific rationale 
for the use of statins as immunomodulators after organ transplantation.