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* Medical R&D Center, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Honkomagome, Bunkyo-ku, Tokyo, Japan;
Intractable Immune System Disease Research Center,
Department of Pathology, and
Department of Immunology, Tokyo Medical University, Shinjuku, Shinjuku-ku, Tokyo, Japan;
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Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki, Noda-shi, Chiba, Japan;
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Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;
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Breast Surgical Oncology Center, Double-Barred Cross Hospital, Japan Anti-Tuberculosis Association, Matuyama, Kiyose-shi, Tokyo, Japan; and
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Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
IL-27 is a novel IL-6/IL-12 family cytokine playing an important role in the early regulation of Th1 responses. We have recently demonstrated that IL-27 has potent antitumor activity, which is mainly mediated through CD8+ T cells, against highly immunogenic murine colon carcinoma. In this study, we further evaluated the antitumor and antiangiogenic activities of IL-27, using poorly immunogenic murine melanoma B16F10 tumors, which were engineered to overexpress single-chain IL-27 (B16F10 + IL-27). B16F10 + IL-27 cells exerted antitumor activity against not only s.c. tumor but also experimental pulmonary metastasis. Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-
knockout mice. In NOD-SCID mice, these activities were decreased, but were still fairly well-retained, suggesting that different mechanisms other than the immune response are also involved in the exertion of these activities. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. Moreover, B16F10 + IL-27 cells clearly inhibited angiogenesis by dorsal air sac method, and IL-27 exhibited dose-dependent inhibition of angiogenesis on chick embryo chorioallantoic membrane. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN--inducible protein (IP-10) and monokine induced by IFN-. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN- was detected at the s.c. B16F10 + IL-27 tumor site, and antitumor activity of IL-27 was partially inhibited by the administration of anti-IP-10. These results suggest that IL-27 possesses potent antiangiogenic activity, which plays an important role in its antitumor and antimetastatic activities.
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