HUMAN MONONUCLEAR CELL-PROLIFERATION, BUT NOT INTERLEUKIN-6 PRODUCTION, IS DEPENDENT ON ISOPRENOID PRODUCTS OF MEVALONATE METABOLISM

Proliferation of mammalian cells is dependent on products of the mevalonate pathway. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types. In this study, we investigated the effects of lovastatin on peripheral blood mononuclear cell (PBMC) proliferation, interleukin-6 (IL-6) synthesis, expression of IL-6 mRNA and leukotriene B-4 synthesis. In the presence of exogenous cholesterol, lovastatin (1-10 mu M) caused a dose-dependent inhibition of PHA stimulated H-3-thymidine incorporation. Most of the lovastatin (5 mu M) inhibition of PBMC was reversed by adding mevalonate (100 mu M), but was unaffected by the addition of exogenous interleukin-2 (IL-2). Lovastatin (5 mu M) did not affect IL-6 synthesis, expression of IL-6 mRNA or the production of leukotriene B-4. In separate experiments, PBMC were cultured with perillic acid (PA), which inhibits the farnesylation of intracellular proteins such as p21 ras. PA caused a dose-dependent inhibition of PHA-stimulated proliferation of PBMC in lovastatin-treated, mevalonate-replete PBMC. Our data suggest that lovastatin inhibits human PBMC proliferation by inhibiting the production of one or more nonsterol isoprenoid intermediates of mevalonate metabolism necessary for IL-2 signal transduction.