Interleukin-18 Acts As an Angiogenesis and Tumor Suppressor

Interleukin-18 (IL-18), also called interferon-gamma (IFN-gamma)-inducing factor, has recently been characterized as a potent IFN-gamma-inducing cytokine. We now report that IL-18 is a novel antiangiogenic and antitumor cytokine. In vitro, IL-18 specifically inhibits fibroblast growth factor-2-stimulated proliferation of capillary endothelial cells. In vivo, IL-18 is sufficiently potent to suppress the fibroblast growth factor-induced corneal neovascularization by systemic administration in mice. This cytokine also inhibits embryonic angiogenesis in the chick chorioallantoic membrane assay. Systemic and intralesional administrations of IL-18 produce a significant suppression of the growth of murine T241 fibrosarcoma in syngeneic C57Bl6/J and immunodeficient SCID mice. The antitumor effect appears to be potent because an average of >75% inhibition of primary tumor growth was observed at a dose of 50 microg/kg/day. In cell culture, murine T241 fibrosarcoma cells are insensitive to recombinant IL-18 at concentrations that significantly inhibit endothelial cell proliferation. Immunohistochemical studies of tumor tissues reveal hypovascularization of the IL-18-treated tumors. These results suggest that IL-18 may participate in the regulation of a switch of tumor angiogenesis.-Cao, R., Farnebo, J., Kurimoto, M., Cao, Y. Interleukin-18 acts as an angiogenesis and tumor suppressor.