The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells.
HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that have been shown to effectively decrease severe rejection periods and development of transplant coronary artery disease after heart transplantation. Precise regulation of major histocompatibility complex class II (MHC class II) gene expression plays a pivotal role in control of the immune response after transplantation. The aim of this study was to evaluate the potential role of HMG-CoA reductase inhibitors in regulating the immune response. We have examined the effects of simvastatin on MHC class II expression in primary human endothelial cells. Using RNAse protection assay and flow cytometry, we observed that simvastatin dose-dependently reduced interferon-gamma (IFN-gamma) induced MHC class II expression (mRNA and protein). In contrast, simvastatin did not affect the expression of MHC class I, pointing to specific actions in the MHC class II signalling cascade. The transcriptional coactivator CIITA is the general regulator of both constitutive and inducible MHC class II expression. After stimulation with IFN-gamma, the CIITA gene is selectively activated via one (promotor IV) of its four promoters. Interestingly, mRNA levels of CIITA were decreased after treatment with simvastatin. In addition, using transient transfections of promoter-reporter constructs we observed that the activity of CIITA promoter IV was decreased by simvastatin. In conclusion, simvastatin selectively decreases IFN-gamma-induced MHC class II expression in human primary endothelial cells through actions on the CIITA promoter IV. Thus, the beneficial effects of statins reported after heart transplantation may result from this immunosuppressive action, suggesting possible therapeutic use for other immunological disorders as well.
Kwak
B
B
Cardiology Division, Department of Medicine, University Hospital, Geneva Medical School, Foundation for Medical Research, Geneva, Switzerland.
Mulhaupt
F
F
Veillard
N
N
Pelli
G
G
Mach
F
F
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D005802:Genes, MHC Class II / Q000187:drug effects*; D017930:Genes, Reporter; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins; D012501:Saphenous Vein; D019821:Simvastatin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D006684:HLA-DR Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D019821:Simvastatin