Dual mode of HMG-CoA reductase inhibition on dendritic cell invasion.

Atherosclerosis is a chronic disease triggered by lipid disturbances, endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to initiate inflammatory immunity. We investigated the role of statins and the mevalonate pathway on DC invasion. DC incubation with atorvastatin (ATV; 0.05-1 microM) for 24h decreased DC adhesion capacity. DC invasion (adhesion/transmigration) was decreased after exposing DCs to low and moderate concentrations of statins, which was reversible by mevalonate (but not geranyl- or farnesyl-pyrophosphate) and cholesterol. Inhibition of the phosphoinositide 3-kinase (with wortmannin) and inhibition of the NO-synthase (with asymmetric dimethyl ADMA) partially reversed statin-mediated effects. High-dose statins markedly decreased DC invasion, which was reversible by adding geranyl pyrophosphate and cholesterol. Inhibition of geranylgeranyltransferase but not inhibition of farnesyltransferase significantly decreased DC invasion. Statin-mediated alteration in DC-cholesterol synthesis and subsequent activation of the Akt/NOS pathway accounts for the statin-induced decrease in DC invasion at low-moderate concentrations (0.05-0.5 microM). Additionally, at high statin concentrations (1 microM) DC invasion is reduced by inhibition of protein geranylgeranylation. As DCs control immunity, regulating DC/endothelial cell interaction by statins may have relevance to inflammation and atherogenesis.