Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase cataly ses the rate limiting step in cholesterol biosynthesis and is markedly inhi bited by the statin family of drugs. The effect of statins on lipid lowerin g is clearly defined, bur the ability of the drugs to directly regulate inf lammatory functions has not been well explored. In this report, we show tha t there are differences among the statins in their capacity to induce proin flammatory responses both in human monocytes in vitro, and in leukocytes in mice in vivo. Treatment of human monocytes with lipophilic statins alone s timulated the production of MCP-1, IL-8, TNF-alpha and IL-1 beta and marked ly sensitized the cells to subsequent challenge with inflammatory agents. L ipophilic statins also increased the production of reactive oxygen species in monocytes. In contrast, pretreatment of cells with the hydrophilic prava statin did not induce these heightened inflammatory responses. Furthermore, treatment of mice with lipophilic statins caused a markedly higher influx of leukocytes into the inflamed peritoneal cavity following challenge with thioglycollate. Overall, these results demonstrate that the lipophilic stat ins influence a regulatory pathway in monocytes that controls cytokine prod uction and that the statins induce different pro-inflammatory responses bot h in vitro and in vivo. (C) 2001 Elsevier Science B.V. All rights reserved.