Lovastatin Inhibits Interferon-γ-Induced Trypanosoma brucei brucei Proliferation: Evidence for Mevalonate Pathway Involvement

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Abstract
Interferon-gamma (IFN-γ) 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-γ-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 braod concentration range of rIFN-γ. 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-γ at a concentration of 103 U/ml added to 106 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-γat a concentration of 104 U/ml showed no proliferative effect. Addition of mevalonate to this concentration of IFN-γ gave a threefold increase in parasite proliferation. Our data suggest that a low concentration of IFN-γ induces parasite growth,ahigh concentration has the opposite effect, and both these events are regulated by activity or inactivity of the mevalonate pathway.