T Lymphocytes as Targets of Statins: Molecular Mechanisms and Therapeutic Perspectives

Raffaella      Ghittoni; Pietro      Enea Lazzerini; Franco      Laghi Pasini; Cosima   T.   Baldari

Abstract

Statins are cholesterol-lowering drugs extensively used for primary and secondary prevention of cardiovascular events related to hypercholesterolemia. Because of their capacity to inhibit HMG-CoA reductase, statins also block the production of isoprenoids required for post-translational modification of proteins such as Ras superfamily GTPases, which are master regulators in signaling pathways triggered by surface receptors. As such, statins have pleiotropic effects on many cell types. In the immune system, statins harbor strong anti-inflammatory properties, which result from their capacity to interfere with the activation of proinflammatory cells, including macrophages and endothelial cells. More recently, T-lymphocytes have been identified as cellular targets of statins. Here we shall review recent findings, which document an inhibitory activity of statins on T-cell activation, proliferation, differentiation to Th1 cells and migration across the bloodbrain barrier. The therapeutic perspectives of these findings, based on animal models and ongoing clinical trials, will also be discussed.

Keywords: HMG-CoA reductase, prenylation, GTPase, Th1/Th2, autoimmune disease, allograft rejection, animal model, clinical trial