Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes.
Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. EBV latent membrane protein 1 (LMP-1) is required for EBV transformation processes. Interferon regulatory factor 4 (IRF-4) is a transcription factor and has oncogenic potential. We find that high levels of IRF-4 are associated with EBV transformation of human primary B cells in vitro and with EBV type III latency in which LMP-1 is expressed. We show that EBV LMP-1 stimulates IRF-4 expression in B lymphocytes. The stimulation of IRF-4 by LMP-1 requires signaling from LMP-1 and involves cellular NF-kappaB. The growth of EBV-transformed cells is inhibited when IRF-4 is specifically down-regulated. We further demonstrate that IRF-4 knockdown cells have lower proliferation but higher apoptotic rates than control cells. Finally, IRF-4 is expressed in significant numbers of specimens of primary central nervous system (CNS) lymphomas (12/27 [44.4%]), an EBV-associated malignancy. The association between the expression levels of LMP-1 and IRF-4 is statistically significant (P = 0.011) in these CNS lymphomas. Our data suggest that IRF-4 may be a critical factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia.
Xu
Dongsheng
D
Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588, USA.
Zhao
Lingjun
L
Del Valle
Luis
L
Miklossy
Judith
J
Zhang
Luwen
L
D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D017931:DNA Primers; D050835:Interferon Regulatory Factors; D014763:Viral Matrix Proteins; D000099218:Interferon Regulatory Factor-4; C037662:EBV-associated membrane antigen, Epstein-Barr virus