Simvastatin stimulates macrophage interleukin-1β secretion through an isoprenylation-dependent mechanism

Statin treatment inhibits oxidized lipoprotein-induced intracellular lipid accumulation (foam cell formation) and reduces plasma levels of inflammatory markers such as interleukin-1β (IL-1β). The aim of the present study was to determine if simvastatin affected lipid accumulation in macrophages incubated with aggregated low density lipoproteins (AgLDL) and whether simvastatin had a direct effect on cytokine secretion from macrophages. Simvastatin treatment did not inhibit AgLDL-induced macrophage lipid accumulation, but significantly increased the secretion of IL-1β and IL-8 from macrophages, whilst inhibiting the secretion of tumor necrosis factor-α (TNF-α) and having no significant effect on IL-6 secretion. Increased macrophage lipid content did not block statin-induced IL-1β and IL-8 secretion.Simvastatin-stimulated IL-1β secretion from macrophages was inhibited by isoprenoids. We therefore hypothesized that simvastatin stimulated IL-1β secretion by affecting isoprenylation-dependent signaling pathways. Another possible mechanism for affecting such signaling is to impair isoprenoid transfer protein activity with specific inhibitors such as GGTI-297 and FTInhI. This treatment resulted in strong stimulation of IL-1β secretion that was further enhanced when exogenous IL-1β was present at the beginning of treatment. These data suggest an isoprenylation-dependent negative-feedback loop for macrophage IL-1β secretion that is inhibited by statin treatment.