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

Human Epstein-Barr virus (EBV)-negative Burkitt lymphomas cells usually gro w as malignant subcutaneous tumors in athymic mice, but these tumors regres s when the Burkitt cells are injected in conjunction with EBV-positive lymp hoblastoid cells or when the Burkitt cells are transfected with the EBV lat ent membrane protein-1 (LMP-I) gene. Tumor regression is mediated, in part, by murine interferon gamma (IFN-y) and the IFN-gamma -induced murine chemo kine IFN-gamma -inducible protein-10 (IP-10), The mechanisms by which EBV-L IMP-1 promotes the expression of IFN-y has remained unclear. Here we show t hat murine interleukin (IL)-18 was consistently expressed in regressing Bur kitt tumors but was either expressed at low levels or absent from progressi vely growing Burkitt tumors. By immunohistochemical methods, IL-18 protein was visualized in regressing but not in progressively growing Burkitt tumor s, In contrast, IL-12 p35 and IL-12 p40 were only rarely expressed in regre ssing Burkitt tumors. In splenocyte cultures, EBV-infected lymphoblastoid c ells and LMP-1-transfected Burkitt cells promoted the expression of IL-18 b ut not the expression of IL-12 p35 and IL-12 p40. A neutralizing antibody d irected at murine IL-18 reduced murine IP-10 expression induced by EBV-immo rtalized cells in splenocyte cultures. These results pro,ide evidence for I L-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 express ion, thereby contributing to tumor regression.