We have examined the effects of tumor necrosis factor alpha (TNFalpha) and its second messenger, ceramide, on HMGCoA reductase, the rate-limiting enzyme in the mevalonate pathway. Treatment of human U-937 and HL-60 cells with TNFalpha or C2-ceramide inhibited both expression and activity of HMGCoA reductase in a time-dependent manner. Maturation of p21(ras) was also inhibited in a mevalonate-dependent fashion. The addition of mevalonate to both U-937 and HL-60 cells could also partially prevent TNFa and ceramide-induced apoptosis. These results support the hypothesis that the inhibition of HMGCoA reductase expression and the subsequent decrease in prenylation of proteins such as p21(ras) are part of the mechanism by which TNFalpha induces apoptosis in these cells. (C) 2002 Elsevier Science (USA). All ights reserved.