Modulating T cell signaling cascades by HMG‐CoA reductase inhibitors

Abstract

AbstractThe modulation of undesirable immune responses is a novel and exciting property of statins. These drugs were initially designed to lower lipid levels by specifically inhibiting the rate‐limiting enzyme HMGCR (3‐hydroxy‐3‐methylglutaryl (HMG)‐CoA reductase; EC 1.1.1.88; standard protein abbreviation HMG‐CoA reductase), which is important for cholesterol synthesis. Various mechanisms accounting for the anti‐inflammatory properties of statins have been proposed: preliminary studies reported an interference in MHC class II presentation necessary for transmitting antigen‐specific signals to T cells but subsequently a direct impact on various intracellular T cell molecules independent of antigen presentation or T cell receptor triggering was also reported. Several groups including ours have recently reported the benefits of treating various animal models of T cell‐mediated autoimmune disorders such as multiple sclerosis and rheumatoid arthritis with HMGCR inhibitors. Although a plethora of molecular processes have been reported, the main biological alterations responsible for modulating T cell response by statins involve (I) a direct interference in T cell cycle progression and induction of anergy and (II) a shift in the differentiation status of T‐helper (Th) effector cells towards a regulatory phenotype. The impact of statins on the T cellular immune response is discussed here in detail.