Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductaseinhibitors

Background Graft vascular disease, a major cause of late graft failure in c ardiac transplant patients, is associated with the presence of class II maj or histocompatibility complex molecules on the endothelium, 3-hydroxy-3-met hylglutaryl (HMG)-CoA reductase inhibitors, e.g., simvastatin, have been sh own to reduce the incidence of graft vascular disease. We studied the effec t of simvastatin on interferon (IFN)-gamma -induced human leukocyte antigen (HLA)-DR expression in human microvascular endothelial cells (MVECs), Methods and Results, Simvastatin pretreatment inhibited MVEC HLA-DR inducti on by IFN-gamma, as detected by flow cytometry, Simvastatin's inhibitory ef fect was reversed by the cholesterol synthesis pathway intermediates mevalo nate and geranylgeranyl pyrophosphate but not squalene, indicating the invo lvement of protein prenylation in this process. Reverse transcription-polym erase chain reaction analysis demonstrated that induction of class II trans activator (CIITA), and consequently, HLA-DR alpha mRNA, is abrogated by sim vastatin, Although signal transducer and activator of transcription (STAT)- 1 is a critical CIITA gene transactivator, immunofluorescence studies, West ern blotting, and electrophoretic mobility shift assays demonstrated that I FN-gamma -induced STAT-I phosphorylation, nuclear translocation, and DNA bi nding are not affected by simvastatin, However, simvastatin inhibited IFN-g amma -induced transactivation of a CIITA promoter IV reporter construct, in dicating the involvement of this promoter in the inhibitory effect of simva statin, Conclusions, Simvastatin pretreatment inhibits CIITA and consequent HLA-DR induction by IFN-gamma in MVECs through interference with protein prenylati on, This inhibitory effect occurs at the level of transcription and is dire cted, at least in part, at the CIITA promoter TV. These results explain som e of the beneficial effects of HMG-CoA reductase inhibitors in cardiac tran splantation.