JVI Accepts, published online ahead of print on 16 April 2008

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, D. Articles by Zhang, L. Search for Related Content PubMed PubMed Citation Articles by Xu, D. Articles by Zhang, L.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.00163-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Interferon regulatory factors 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes

Dongsheng Xu, Lingjun Zhao, Luis Del Valle, Judith Miklossy, and Luwen Zhang^*

Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68588; Institute for Molecular Virology, Saint Louis University, St. Louis, MO 63104; Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122

^* To whom correspondence should be addressed. Email: lzhang2{at}unlnotes.unl.edu.

Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. The 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 an 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 the signaling from LMP-1 and involves cellular NF-B. 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.

This article has been cited by other articles:

• Crowther-Swanepoel, D., Houlston, R. S. (2009). The molecular basis of familial chronic lymphocytic leukemia. haematol 94: 606-609 [Full Text]  
• Shaffer, A. L., Emre, N.C. T., Romesser, P. B., Staudt, L. M. (2009). IRF4: Immunity. Malignancy! Therapy?. Clin. Cancer Res. 15: 2954-2961 [Abstract] [Full Text]  
• Wies, E., Hahn, A. S., Schmidt, K., Viebahn, C., Rohland, N., Lux, A., Schellhorn, T., Holzer, A., Jung, J. U., Neipel, F. (2009). The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5. J. Biol. Chem. 284: 8525-8538 [Abstract] [Full Text]