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

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

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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-κB. 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.

Original languageEnglish (US)
Pages (from-to)6251-6258
Number of pages8
JournalJournal of virology
Volume82
Issue number13
DOIs
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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