ABSTRACT
INTRODUCTION: In liver transplant recipients with Epstein-Barr virus (EBV) disease, we reported a low rate of acute rejection after stopping or markedly lowering immunosuppression. This observation led to the hypothesis that EBV, as a means of viral persistence, induces expression of antiapoptotic factors and these factors, in turn, confer protection to the transplanted organ. Bcl-2, an antiapoptotic factor induced by EBV in various host cells, is not normally expressed in the liver. We questioned whether bcl-2 is expressed in the transplanted liver and whether its expression is modified by EBV. MATERIALS AND METHODS: Retrospective liver biopsy specimen from liver transplant patients diagnosed with EBV (n=12) were examined for the presence of bcl-2 by immunohistochemistry and compared with EBV (-) transplant (n=15), and nontransplant (n=13) livers. RESULTS: The most significant finding was the presence of endothelial bcl-2 expression in the majority of EBV (+) transplant samples examined (67%) and its relative absence in the other two groups (P<0.005). There was also bcl-2 expression in the hepatocytes and lymphocytes of the majority of transplant liver samples, irrespective of EBV status. DISCUSSION: We have identified a strong association between EBV infection and endothelial bcl-2 expression in transplant livers. We also found that transplantation, in itself, was associated with bcl-2 expression in the hepatocytes and lymphocytes of liver allografts.
Subject(s)
Endothelium, Vascular/chemistry , Epstein-Barr Virus Infections/etiology , Liver Transplantation/adverse effects , Proto-Oncogene Proteins c-bcl-2/analysis , Graft Rejection , Hepatocytes/chemistry , Humans , Lymphocytes/chemistry , Retrospective Studies , Transplantation, HomologousSubject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 CYP1A1/drug effects , Dioxins/pharmacology , Polychlorinated Dibenzodioxins/pharmacology , Receptors, Aryl Hydrocarbon , Animals , Aryl Hydrocarbon Receptor Nuclear Translocator , Basic Helix-Loop-Helix Transcription Factors , Chromatin , Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A2/biosynthesis , Cytochrome P-450 CYP1A2/drug effects , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP1B1 , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/genetics , DNA-Binding Proteins/metabolism , Enhancer Elements, Genetic/genetics , Enzyme Induction , Female , Gene Expression Regulation, Enzymologic , Glutathione Transferase/biosynthesis , Glutathione Transferase/drug effects , Male , NADH, NADPH Oxidoreductases/biosynthesis , NADH, NADPH Oxidoreductases/drug effects , Pharmaceutical Preparations/metabolism , Promoter Regions, Genetic/genetics , Rats , Transcription Factors/metabolism , Transcriptional ActivationABSTRACT
The induction of microsomal cytochrome P4501A1 by polycyclic aromatic hydrocarbons represents an interesting response by which mammalian cells adapt to xenobiotic exposure. Enzyme induction reflects increased transcription of the corresponding CYP1A1 gene. Analyses of the induction mechanism using genetic, biochemical, and molecular biological approaches have revealed a novel transcriptional regulatory pathway that involves ligand-dependent heterodimerization between two basic helix-loop-helix proteins (the Ah receptor and Arnt), interaction of the heterodimer with a xenobiotic-responsive enhancer, transmission of the induction signal from the enhancer to the CYP1A1 promoter, and alterations in chromatin structure. Current techniques permit examination of the induction mechanism in intact cells and analyses of the CYP1A1 gene in its native chromosomal configuration. Such experiments generate new insights into the control of mammalian transcription that are of relatively broad interest.
