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

在对实验性无胸腺小鼠模型的其他研究过程中， 肿瘤消退与广泛的组织坏死相关， 内皮细胞损伤和血管内血栓形成 这 表明组织缺血可能是肿瘤消退的核心， 并认为不平衡的血管生成可能是肿瘤发生的原因， 回归分析 细胞因子在消退肿瘤中的表达分析 组织显示存在多种炎性细胞因子， 包括TNF-α和IL-6，此外， 细胞因子IL-12（p35和p40链）和α趋化因子 IP-10和米格。 这些化学细胞的生物学特性 还不完全了解。我们测试了IP-10，阿尔法成员， 趋化因子家族，可能作为血管生成的抑制剂，并发现 IP-10能显著抑制碱性成纤维细胞生长因子 （FGF）诱导的体内新血管形成。 此外，IP-10 剂量依赖性抑制内皮细胞分化为肾小管 体外毛细血管结构。 IP-10对内皮细胞增殖无抑制作用， 增殖，表明生长抑制不是主要的 IP-10作为血管生成抑制剂的作用机制。 因此，在本发明中， 这些研究证明了IP-10的重要生物学特性， 提出了IP-10可能参与监管的可能性， 肿瘤发生过程中的血管生成。 因为IP-10是一种γ干扰素 诱导型趋化因子，人们希望它被诱导，无论何时 存在干扰素-γ。 最近的报告表明，IL-12可以作为 一种有效的体内血管生成抑制剂， IL-12可能通过诱导间接发挥这种生物学特性 干扰素γ其次是IP-10 我们发现 给予干扰素-γ或IP-10的抗体 中和IL-12对新生血管的抑制作用， vivo. 此外，IL-12诱导IP-10在未纯化的细胞中表达。 表明IL-12可诱导IP-10表达 在某些细胞中。 因此，这些结果证明了 IP-10作为介导IL-12抑制血管生成的介质，并提高 IP-10也可能有助于抗肿瘤作用， IL-12.A.安焦利略角Sgadari，D. D. Taub，F. Liao，J.M. Farber，S. Maleshwari，H.K. Klinman，G.H. Reaman和G.土佐人 干扰素诱导蛋白10是一种有效的血管生成抑制剂， Vivo. J. Exp. 182：155-162，1995 Sgadari C.，Angiolillo AL，以及 Tosato，G.白细胞介素-12对血管生成的抑制作用是由 干扰素诱导蛋白10 Blood 87：3877-82，1996

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