Abstract
Sepsis, which is the product of a poorly controlled inflammatory response, is a major health problem. Adequate therapies for sepsis are unavailable, and patient care is mainly supportive. Statins, widely used for the treatment of hypercholesterolemia, have been found to be antiinflammatory, but the mechanisms responsible for this alteration in the inflammatory response are not well understood. We investigated the effect of statins on CD14 expression, the major binding site for bacterial lipopolysaccharide (LPS) on the macrophage surface. CD14 is found in both a membrane-bound form on the cell surface (mCD14) and in a soluble variant in circulation (sCD14). Treatment of RAW 264.7 macrophages with lovastatin resulted in elevated mCD14 levels and decreased sCD14 levels after LPS stimulation. The increase in mCD14 was dependent on depletion of geranylgeranyl pyrophosphate (GGPP) and subsequent inhibition of Rho GTPases, whereas the effect of lovastatin on sCD14 was independent of this pathway. The increase in mCD14 expression correlated with an enhanced response to LPS, at least at the level of tumor necrosis factor (TNF)-alpha secretion. These results suggest that statin treatment can modulate macrophage functon, which may have an impact on inflammation and the outcome from sepsis.