EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines.
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.
Tsai
Shu-Chun
SC
Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. chtsai@ntu.edu.tw
Lin
Sue-Jane
SJ
Chen
Po-Wen
PW
Luo
Wen-Yi
WY
Yeh
Te-Huei
TH
Wang
Hsei-Wei
HW
Chen
Chi-Ju
CJ
Tsai
Ching-Hwa
CH
D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D001483:Base Sequence; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D006689:Hodgkin Disease / Q000209:etiology; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000209:etiology; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015533:Transcriptional Activation
C063676:BZLF1 protein, Herpesvirus 4, Human; D017931:DNA Primers; D004279:DNA, Viral; D018793:Interleukin-13; D015534:Trans-Activators