The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHCclass II expression in human vascular endothelial cells - Statins as a potential novel immunosuppressive agent

HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that ha ve been shown to effectively decrease severe rejection periods and developm ent of transplant coronary artery disease after heart transplantation. Prec ise regulation of major histocompatibility complex class II (MIC class II) gene expression pla;vs a pivotal role in control of the immune response aft er transplantation. The aim of this study was to evaluate the potential rol e of HMG-CoA reductase inhibitors in regulating the immune response. We hav e examined the effects of simvastatin on A IHC class II expression in prima ry human endothelial cells. Using RNAse protection assay and flow cytometry , we observed that simvastatin dose-dependently reduced interferon-gamma (I FN-gamma) induced MHC class II expression (mRNA and protein). In contrast, simvastatin did not affect the expression of MHC class I, pointing to speci fic actions in the A IHC class II signalling cascade. The transcriptional c oactivator CIITA is the general regulator of both constitutive and inducibl e MHC class II expression, after stimulation with IFN-gamma, the CIITA gene is selectively activated via one (promoter IV) of its four promoters. Inte restingly, mRNA levels of CIITA were decreased after treatment with simvast atin. In addition, using transient transfections of promoter-reporter const ructs we observed that the activity of CIITA promoter IV was decreased by s imvastatin. In conclusion, simvastatin selectively decreases IFN-gamma -ind uced MHC class II expression in human primary endothelial cells through act ions on the CIITA promoter IV. Thus, the beneficial effects of statins repo rted after heart transplantation may result from this immunosuppressive e a ction, suggesting possible therapeutic use for other immunological disorder s as well.