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(The FASEB Journal. 1999;13:2195-2202.)
© 1999 FASEB

Interleukin-18 acts as an angiogenesis and tumor suppressor

RENHAI CAO*, JACOB FARNEBO*, MASASHI KURIMOTO{dagger} and YIHAI CAO*1

* Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden; and
{dagger} Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama 702, Japan

1Correspondence: Yihai Cao, M.D., Ph.D., Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail: yihai.cao{at}mtc.ki.se

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 µg/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.


Key Words: neovascularization • antitumor • interferon-{gamma}




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Copyright © 1999 by The Federation of American Societies for Experimental Biology.