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 meval onate pathway. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metab olites, and has been shown to inhibit proliferation of several cell ty pes. In this study, we investigated the effects of lovastatin on perip heral 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 incorporat ion. Most of the lovastatin (5 mu M) inhibition of PBMC was reversed b y 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 (P A), which inhibits the farnesylation of intracellular proteins such as p21 ras. PA caused a dose-dependent inhibition of PHA-stimulated prol iferation of PBMC in lovastatin-treated, mevalonate-replete PBMC. Our data suggest that lovastatin inhibits human PBMC proliferation by inhi biting the production of one or more nonsterol isoprenoid intermediate s of mevalonate metabolism necessary for IL-2 signal transduction.