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Blood, 2 July 2009, Vol. 114, No. 1, pp. 109-118.
Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2008-12-193375.


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LYMPHOID NEOPLASIA

EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines

Shu-Chun Tsai1, Sue-Jane Lin1,2, Po-Wen Chen1, Wen-Yi Luo1, Te-Huei Yeh3, Hsei-Wei Wang4, Chi-Ju Chen4, and Ching-Hwa Tsai1

1 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei; 2 Immunology Research Center, National Health Research Institutes, Miaoli; 3 Department of Otolaryngology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei; and 4 Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan

Epstein-Barr virus (EBV) infection can modify the cytokine expression profiles of host cells and determine the fate of those cells. Of note, expression of interleukin-13 (IL-13) may be detected in EBV-associated Hodgkin lymphoma and the natural killer (NK) cells of chronic active EBV-infected patients, but its biologic role and regulatory mechanisms are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells early during EBV infection. Furthermore, the EBV lytic protein, Zta (also known as the BZLF-1 product), which is a transcriptional activator, was found to induce IL-13 expression following transfection. Mechanistically, induction of IL-13 expression by Zta is mediated directly through its binding to the IL-13 promoter, via a consensus AP-1 binding site. Blockade of IL-13 by antibody neutralization showed that IL-13 is required at an early stage of EBV-induced proliferation and for long-term maintenance of the growth of EBV immortalized lymphoblastoid cell lines (LCLs). Thus, Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of EBV-associated lymphoproliferative disorders, such as posttransplantation lymphoproliferative disease (PTLD) and Hodgkin lymphoma.


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