Regulation of different inflammatory diseases by impacting the mevalonate pathway

Abstract

The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) interfere with the mevalonate pathway. While initially developed for their lipid-lowering properties, statins have been extensively investigated with respect to their impact on autoantigen and alloantigen driven immune responses. Mechanistically it was shown that statins modify immune responses on several levels, including effects on dendritic cells, endothelial cells, macrophages, B cells and T cells. Several lines of evidence suggest that statins act in a disease-specific manner and are not effective in each immune disorder. This review discusses possible modes of action of statins in modulating immunity towards autoantigens and alloantigens.

Figure 1

Inhibition of the l-mevalonate pathway for immunomodulation. Statins interfere with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the l-mevalonate pathway which causes reduction of farnesylated and geranylgeranylated downstream proteins. Besides others, the GTPases Ras, Rho-B and Rap-1 that play a role in the process of activation and proliferation of T cells are not prenylated, which affects their binding to the T-cell membrane. This shift in active GTPase signalling is connected to a blockade of T helper type 1 (Th1) cytokine production.