Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors.
BACKGROUND
Graft vascular disease, a major cause of late graft failure in cardiac transplant patients, is associated with the presence of class II major histocompatibility complex molecules on the endothelium. 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, e.g., simvastatin, have been shown to reduce the incidence of graft vascular disease. We studied the effect of simvastatin on interferon (IFN)-gamma-induced human leukocyte antigen (HLA)-DR expression in human microvascular endothelial cells (MVECs).


RESULTS
Simvastatin pretreatment inhibited MVEC HILA-DR induction by IFN-gamma, as detected by flow cytometry. Simvastatin's inhibitory effect was reversed by the cholesterol synthesis pathway intermediates mevalonate and geranylgeranyl pyrophosphate but not squalene, indicating the involvement of protein prenylation in this process. Reverse transcription-polymerase chain reaction analysis demonstrated that induction of class II transactivator (CIITA), and consequently, HLA-DRalpha mRNA, is abrogated by simvastatin. Although signal transducer and activator of transcription (STAT)-1 is a critical CIITA gene transactivator, immunofluorescence studies, Western blotting, and electrophoretic mobility shift assays demonstrated that IFN-gamma-induced STAT-1 phosphorylation, nuclear translocation, and DNA binding are not affected by simvastatin. However, simvastatin inhibited IFN-gamma-induced transactivation of a CIITA promoter IV reporter construct, indicating the involvement of this promoter in the inhibitory effect of simvastatin.


CONCLUSIONS
Simvastatin pretreatment inhibits CIITA and consequent HLA-DR induction by IFN-gamma in MVECs through interference with protein prenylation. This inhibitory effect occurs at the level of transcription and is directed, at least in part, at the CIITA promoter IV. These results explain some of the beneficial effects of HMG-CoA reductase inhibitors in cardiac transplantation.
Sadeghi
M M
MM
Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut 06520, USA.
Tiglio
A
A
Sadigh
K
K
O'Donnell
L
L
Collinge
M
M
Pardi
R
R
Bender
J R
JR
D002784:Cholesterol / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005802:Genes, MHC Class II / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D002784:Cholesterol; D019821:Simvastatin