The pleiotropic effect of statins on immune cell function
In this thesis, the pleiotropic effects of statins on the disruption of prenylation and membrane rafts were investigated in immune effector cells. T cells and NK cells were extracted from various groups of patients treated with statins and proliferation and cytotoxicity respectively, measured ex vivo. In a study of patients with cardiovascular disease, a 23% reduction in T cell proliferation and 43% reduction in NK cytotoxicity were observed. In a normal volunteer study where healthy subjects received simvastatin (40mg per day) for 4 weeks, a comparable reduction in T cell proliferation was not apparent, however a 30% reduction in NK cytotoxicity was observed. In vitro statin treatment further reduced proliferation and cytotoxicity whereas addition of farnesyl and geranylgeranyl transferase inhibitors had little or no effect. In conclusion, this thesis has demonstrated that statins have a multitude of applications and effects. The pleiotropism of statins due to reduced prenylation was observed in vitro by western blot in multiple signalling pathways and confirmed with the use of FT and GGT inhibitors in these pathways. However, the lack of functional effect of FT and GGTIs indicated that prenylation has a lesser impact on the functions of immune effector cells than cholesterol depletion of rafts. The comparable results obtained with MßCB indicated that the reduction of cholesterol in the membrane by statins was disrupting rafts and therefore disrupting signalling pathways to a greater extent than prenylation inhibition. It is however likely to be a combination of both processes that contributes to the pleiotrophic effect of statins.