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

IL-2 和 IP-10 是血管生成的有效调节剂

• 批准号: 2456635
• 负责人: G TOSATO
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2456635
• 关键词: angiogenesis; athymic mouse; chemokine; growth inhibitors; immunomodulators; immunoregulation; interferon gamma; interleukin 12; neoplasm /cancer remission /regression

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

在对实验性无瘤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中心， 并提出血管生成失衡可能是肿瘤的原因。 回归。细胞因子在退行性肿瘤中的表达分析 组织显示存在多种炎性细胞因子， 包括肿瘤坏死因子-α和白介素6，此外，还存在 细胞因子IL-12(包括p35和p40链)和α-趋化因子 IP-10和Mig.这些是趋化因子，它们的生物学特性是 仍然不完全清楚。我们测试了IP-10，阿尔法的成员 趋化因子家族，可能作为血管生成的抑制因子，并发现 IP-10对碱性成纤维细胞生长因子的深刻抑制作用 成纤维细胞生长因子诱导体内新生血管形成。此外，IP-10 剂量依赖性抑制内皮细胞向小管分化 体外培养的毛细血管结构。IP-10对内皮细胞无抑制作用 增殖，表明生长抑制不是主要的 IP-10作为血管生成抑制因子的机制。因此， 这些研究记录了IP-10的一个重要生物学特性，以及 提高IP-10可能参与调节的可能性 肿瘤发生过程中的血管生成。因为IP-10是一种干扰素-伽马 可诱导的趋化因子，人们期望它在任何时候被诱导 存在干扰素-伽马抗体。最近有报道称，IL-12可以作为 体内一种有效的血管生成抑制剂增加了这样一种可能性 IL-12可能通过诱导间接发挥这一生物学特性。 干扰素伽玛，其次是IP-10。我们发现 干扰素-γ或IP-10抗体的注射 中和IL-12对兔血管新生的抑制作用 活着。此外，IL-12可诱导未纯化细胞IP-10的表达 淋巴细胞亚群，表明IL-12可诱导IP-10的表达 在某些细胞中。因此，这些结果证明了 IP-10作为IL-12抑制血管生成的介导物，并提高 IP-10也可能参与其抗肿瘤作用 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊细介绍 干扰素诱导蛋白10是一种有效的血管生成抑制因子 活着。J.Exp.地中海医院。182：155-162,1995 Sgadari C.，Angiolillo AL，和 白介素12对血管生成的抑制作用是通过 干扰素诱导蛋白10.血液87：3877-82,1996