IL-2 AND IP-10 ARE POTENT REGULATORS OF ANGIOGENESIS

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In the course of other studies on an experimental athymic mouse model, tumor regression was associated with extensive tissue necrosis associated with endothelial cell damage and intravascular thrombosis. This suggested that tissue ischemia might be central to tumor regression, and suggested that unbalanced angiogenesis might be responsible for tumor regression. Analysis of cytokine expression in the regressing tumor tissues showed the presence of a variety of inflammatory cytokines, including TNF-alpha and IL-6, and, in addition, presence of the the cytokine IL-12 (both p35 and p40 chains) and of the alpha chemochines IP-10 and Mig. These are chemochines whose biological properties are still incompletely known. We tested whether IP-10, a member of the alpha chemokine family, might act as an inhibitor of angiogenesis, and found that IP-10 profoundly inhibits basic fibroblast growth factor (FGF)-induced neovascularization in vivo. In addition, IP-10 dose-dependently suppressed endothelial cell differentiation into tubular capillary structures in vitro. IP-10 did not inhibit endothelial cell proliferation, indicating that growth inhibition is not the primary mechanism by which IP-10 acts as an inhibitor of angiogenesis. Thus, these studies document an important biological property of IP-10, and raise the possibility that IP-10 may participate in the regulation of angiogenesis during tumorigenesis. Because IP-10 is an interferon-gamma inducible chemokine, one would expect it to be induced whenever interferon-gamma is present. The recent report that IL-12 can act as a potent inhibitor of angiogenesis in vivo raised the possibility that IL-12 may exert this biological property indirectly, through induction of interferon gamma and, secondarily, IP-10. We found that administration of antibodies to either interferon-gamma or IP-10 neutralized the inhibitory effects of IL-12 on neovascularization in vivo. In addition, IL-12 induced IP-10 expression in unpurified lymphocyte populations, indicating that IL-12 can induce IP-10 expression in certain cells. Thus, these results document the important role of IP-10 as a mediator of angiogenesis inhibition by IL-12, and raise the possibility that IP-10 may also contribute to the antitumor effect of IL-12.A. Angiolillo, C. Sgadari, D.D. Taub, F. Liao, J.M. Farber, S. Maleshwari, H.K. Klinman, G.H. Reaman, and G. Tosato Human Interferon-inducible Protein 10 is a Potent Inhibitor of Angiogenesis in Vivo. J. Exp. Med. 182: 155-162, 1995 Sgadari C., Angiolillo AL, and Tosato, G. Inhibition of Angiogenesis by Interleukin-12 is mediated by the Interferon-Inducible Protein 10. Blood 87:3877-82, 1996