Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells

Epstein-Barr virus (EBV)-associated, undifferentiated type of nasopharyngeal carcinoma (NPC) is characterized by intensive leukocyte infiltration. Interaction between the infiltrating cells and the tumor cells has been considered crucial for NPC development. Recruitment of the infiltrates can be directed by certain chemokines present in the NPC tissues. It is unknown whether and how EBV lytic infection regulates expression of the chemokines. Using an antibody array, we first found that several chemokines secreted from EBV-infected NPC cells are increased upon EBV reactivation into the lytic cycle, and interleukin-8 (IL-8) is the chemokine upregulated most significantly and consistently. Further studies showed that the EBV lytic transactivator Zta is a potent inducer of IL-8 in NPC cells, augmenting secreted and intracellular IL-8 proteins, as well as IL-8 RNA. Zta upregulates Egr-1, a cellular transcription factor that has been involved in upregulation of IL-8, but the Zta-induced IL-8 expression is independent of Egr-1. The ability of Zta to transactivate the IL-8 promoter is important for the induction of IL-8, and we have identified two Zta-responsive elements in the promoter. Zta can bind to these two elements in vitro and can also be recruited to the IL-8 promoter in vivo. DNA-binding-defective Zta mutants can neither activate the IL-8 promoter nor induce IL-8 production. In addition, Zta-expressing NPC cells exert enhanced chemotactic activity that is mainly mediated by IL-8. Since IL-8 may contribute to not only leukocyte infiltration but also multiple oncogenic processes, the present study provides a potential link between EBV lytic infection and pathogenesis of NPC.