Antiangiogenic and antitumor activities of IL-27.
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-gamma 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-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-gamma 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.
Shimizu
Motomu
M
Medical R&D Center, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Honkomagome, Bunkyo-ku, Japan.
Shimamura
Mariko
M
Owaki
Toshiyuki
T
Asakawa
Masayuki
M
Fujita
Koji
K
Kudo
Motoshige
M
Iwakura
Yoichiro
Y
Takeda
Yasutaka
Y
Luster
Andrew D
AD
Mizuguchi
Junichiro
J
Yoshimoto
Takayuki
T
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002642:Chick Embryo; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011994:Recombinant Proteins / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C486767:Il27 protein, mouse; D007378:Interleukins; C464565:MYDGF protein, human; D011994:Recombinant Proteins; D007371:Interferon-gamma