Lovastatin inhibits interferon-gamma-induced Trypanosoma brucei brucei proliferation: evidence for mevalonate pathway involvement.

Interferon-gamma (IFN-gamma) is an essential immunoregulating molecule that has recently been shown to have a growth stimulatory effect on Trypanosoma brucei brucei (T. b. brucei). The signalling pathway(s) involved during this triggering are unknown. Since the different products from the biosynthesis pathway utilizing mevalonate have several important cellular functions, ranging from cholesterol synthesis to growth control, we here investigate the possible role for the mevalonate pathway in IFN-gamma-driven parasite proliferation. Thus, lovastatin, a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase-inhibiting drug, was incubated at different concentrations in vitro with T. b. brucei. The parasites were then stimulated with a broad concentration range of rIFN-gamma. The effect on proliferation or growth was measured either by the tritium-labeled thymidine incorporation assay or by direct counting of parasites from the cultures using light microscopy. The maximum proliferative response was obtained with IFN-gamma at a concentration of 10(3) U/ml added to 10(6) parasites. This response was markedly decreased with lovastatin, even at a low concentration (0.1 mM). The effect of lovastatin was reversed by the addition of 10 mM mevalonate. IFN-gamma at a concentration of 10(4) U/ml showed no proliferative effect. Addition of mevalonate to this concentration of IFN-gamma gave a threefold increase in parasite proliferation. Our data suggest that a low concentration of IFN-gamma induces parasite growth, a high concentration has the opposite effect, and both these events are regulated by activity or inactivity of the mevalonate pathway.