Epstein-Barr virus latent membrane protein 1 activates nuclear factor-kappa B in human endothelial cells and inhibits apoptosis.
BACKGROUND
Although vascular changes and transplant vasculopathy have been described with cytomegalovirus, the impact of Epstein-Barr virus (EBV) on the vascular endothelium of the transplanted allograft is largely unknown. We recently reported that EBV (+) patients taken off immunosuppressive medications for periods of time had a low incidence of chronic rejection. In another report, we noted that there was expression of the "protective" antiapoptotic factor Bcl-2 in the vascular endothelium of transplant allografts from EBV (+) patients. In this report, we determined the effect of latent EBV infection on endothelial cell activation and apoptosis.


METHODS
Cultured human umbilical vein endothelial cells (HUVEC) were either infected with EBV or transduced with EBV latent membrane protein 1 and examined for apoptosis, nuclear factor (NF)-kappaB activation, and expression of chemokines, cytokines, and adhesion molecules.


RESULTS
EBV infection and latent membrane protein 1 expression in HUVEC resulted in NF-kappaB activation and increased expression of the cytokines interleukin (IL)-1alpha, IL-1beta, and IL-6; the chemokines IL-8, monocyte chemotactic protein-1, and RANTES; and the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. There was increased expression of the antiapoptotic genes A1, c-IAP2, and TRAF1; inhibition of caspase 3; and protection from apoptosis.


CONCLUSIONS
Latent EBV in HUVEC results in constitutive NF-kappaB activation, protection from apoptosis, and increased basal expression of inflammatory factors. The in vivo effect of latent EBV in the vascular endothelium of the transplanted allograft and its resultant impact on transplant vasculopathy are the subject of further investigations in our laboratory.
Xiong
Anming
A
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA.
Clarke-Katzenberg
Regina H
RH
Valenzuela
Glenn
G
Izumi
Kenneth M
KM
Millan
Maria T
MT
D017209:Apoptosis; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D020031:Epstein-Barr Virus Infections / Q000473:pathology / Q000503:physiopathology*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D047990:TNF Receptor-Associated Factor 1; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics*
D018925:Chemokines; D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D014763:Viral Matrix Proteins