Inhibition of interferon-γ-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-COA reductase inhibitors1

Mehran M. Sadeghi, Andrea Tiglio, Kaveh Sadigh, Lynn O'Donnell, Mark Collinge, Ruggero Pardi, Jeffrey R. Bender

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Background. Graft vascular disease, a major cause of late graft failure in cardiac transplant patients, is associated with the presence of class II major histo-compatibility 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)-γ-induced human leukocyte antigen (HLA)-DR expression in human microvascular endothelial cells (MVECs). Methods and Results. Simvastatin pretreatment inhibited MVEC HLA-DR induction by IFN-γ, 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-DRα 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-γ-induced STAT-1 phosphorylation, nuclear translocation, and DNA binding are not affected by simvastatin. However, simvastatin inhibited IFN-γ-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-γ 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.

Original languageEnglish
Pages (from-to)1262-1268
Number of pages7
JournalTransplantation
Volume71
Issue number9
Publication statusPublished - May 15 2001

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MHC Class II Genes
Simvastatin
Major Histocompatibility Complex
Interferons
Transcriptional Activation
Oxidoreductases
Endothelial Cells
HLA Antigens
Protein Prenylation
STAT1 Transcription Factor
Transplants
Hydroxymethylglutaryl CoA Reductases
Vascular Diseases
Squalene
Trans-Activators
Electrophoretic Mobility Shift Assay
Heart Transplantation
Reverse Transcription
Endothelium
Fluorescent Antibody Technique

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Inhibition of interferon-γ-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-COA reductase inhibitors1 . / Sadeghi, Mehran M.; Tiglio, Andrea; Sadigh, Kaveh; O'Donnell, Lynn; Collinge, Mark; Pardi, Ruggero; Bender, Jeffrey R.

In: Transplantation, Vol. 71, No. 9, 15.05.2001, p. 1262-1268.

Research output: Contribution to journalArticle

Sadeghi, Mehran M. ; Tiglio, Andrea ; Sadigh, Kaveh ; O'Donnell, Lynn ; Collinge, Mark ; Pardi, Ruggero ; Bender, Jeffrey R. / Inhibition of interferon-γ-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-COA reductase inhibitors1 . In: Transplantation. 2001 ; Vol. 71, No. 9. pp. 1262-1268.
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abstract = "Background. Graft vascular disease, a major cause of late graft failure in cardiac transplant patients, is associated with the presence of class II major histo-compatibility 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)-γ-induced human leukocyte antigen (HLA)-DR expression in human microvascular endothelial cells (MVECs). Methods and Results. Simvastatin pretreatment inhibited MVEC HLA-DR induction by IFN-γ, 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-DRα 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-γ-induced STAT-1 phosphorylation, nuclear translocation, and DNA binding are not affected by simvastatin. However, simvastatin inhibited IFN-γ-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-γ 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.",
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AU - Tiglio, Andrea

AU - Sadigh, Kaveh

AU - O'Donnell, Lynn

AU - Collinge, Mark

AU - Pardi, Ruggero

AU - Bender, Jeffrey R.

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N2 - Background. Graft vascular disease, a major cause of late graft failure in cardiac transplant patients, is associated with the presence of class II major histo-compatibility 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)-γ-induced human leukocyte antigen (HLA)-DR expression in human microvascular endothelial cells (MVECs). Methods and Results. Simvastatin pretreatment inhibited MVEC HLA-DR induction by IFN-γ, 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-DRα 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-γ-induced STAT-1 phosphorylation, nuclear translocation, and DNA binding are not affected by simvastatin. However, simvastatin inhibited IFN-γ-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-γ 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.

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