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(Journal of Leukocyte Biology. 2001;69:779-784.)
© 2001 by Society for Leukocyte Biology

Interleukin-18 expression induced by Epstein-Barr virus-infected cells

Lei Yao*, Joyce Setsuda*, Cecilia Sgadari{dagger}, Barry Cherney{ddagger} and Giovanna Tosato*

* Transplantation Immunology Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, and
{ddagger} Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Bethesda, MD; and
{dagger} Laboratorio di Virologia, Istituto Superiore di Sanitá, Rome, Italy

Correspondence: Lei Yao, Transplantation Immunology Department, Medicine Branch, DCS, NCI, NIH, Bldg. 10, Room 12C07, Bethesda, MD 20892. E-mail: Yaol{at}mail.nih.gov

Human Epstein-Barr virus (EBV)-negative Burkitt lymphomas cells usually grow as malignant subcutaneous tumors in athymic mice, but these tumors regress when the Burkitt cells are injected in conjunction with EBV-positive lymphoblastoid cells or when the Burkitt cells are transfected with the EBV latent membrane protein-1 (LMP-1) gene. Tumor regression is mediated, in part, by murine interferon {gamma} (IFN-{gamma}) and the IFN-{gamma}-induced murine chemokine IFN-{gamma}-inducible protein-10 (IP-10). The mechanisms by which EBV-LMP-1 promotes the expression of IFN-{gamma} has remained unclear. Here we show that murine interleukin (IL)-18 was consistently expressed in regressing Burkitt tumors but was either expressed at low levels or absent from progressively growing Burkitt tumors. By immunohistochemical methods, IL-18 protein was visualized in regressing but not in progressively growing Burkitt tumors. In contrast, IL-12 p35 and IL-12 p40 were only rarely expressed in regressing Burkitt tumors. In splenocyte cultures, EBV-infected lymphoblastoid cells and LMP-1-transfected Burkitt cells promoted the expression of IL-18 but not the expression of IL-12 p35 and IL-12 p40. A neutralizing antibody directed at murine IL-18 reduced murine IP-10 expression induced by EBV-immortalized cells in splenocyte cultures. These results provide evidence for IL-18 expression in response to a viral latency protein and suggest that IL-18 may play an important role as an endogenous inducer of IFN-{gamma} expression, thereby contributing to tumor regression.

Key Words: Burkitt lymphoma • interferon {gamma} • angiogenesis • latent membrane protein-1 • tumor regression




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