IL-2 AND IP-10 AND IL-15 ARE POTENT REGULATORS OF ANGIOGENESIS

IL-12是由巨噬细胞、B细胞系产生的多功能细胞因子 以及刺激T细胞和NK细胞增殖的其他细胞， 增强非特异性细胞溶解功能，诱导干扰素-γ 产生，并促进Th 1型T细胞应答的发展。 在 鼠模型IL-12已经证明具有抗肿瘤、抗微生物和抗肿瘤作用， 抗真菌活性 因为负责 IL-12的抗肿瘤活性在很大程度上是未知的，我们探索了 IL-12可能作为血管生成的抑制剂。 肿瘤 细胞需要吸引新的血管在局部生长， 转移，并且许多血管生成抑制剂具有抗肿瘤作用。 活动 在目前的研究中，我们已经表明IL-12是一种有效的 体内血管生成抑制剂。 我们进一步证明， 作用是通过干扰素γ间接介导的，其次是 IP-10是α趋化因子家族的一员， 体内血管生成抑制剂。 相比之下，IL-15有效地刺激 体内新血管形成，直接作用于内皮细胞。 IL-12目前正在初步临床试验中进行测试，以评估其 作为癌症治疗剂的潜力。临床前研究已经记录了 IL-12可以对多种肿瘤细胞发挥有效的抗肿瘤活性， 实验肿瘤，以及抗微生物和抗真菌活性 对抗各种传染性病原体 虽然IL-12已知存在于 对免疫系统的各种影响解释了其抗微生物 功能，我们对它的抗肿瘤作用的理解是自然的。 它 了解IL-12是如何致癌的是非常重要的， 在设计产品开发时，信息可能至关重要。 在 特别是，这些信息可能有助于预测其毒性。 我们 研究已经证实，IL-12是血管生成的抑制剂， 体内，并进一步确定这种活性是间接的， 通过干扰素-γ介导，其次是IP-10。 过程中 在这些研究中，我们已经开发了用于IL-12的改进的生物学测试， 建立了新的体外和体内模型，以研究影响 关于血管生成。

IL-12 is a multifunctional cytokine produced by macrophages, B cell lines and other cells that stimulates the proliferation of T cells and NK cells, enhances non-specific cytolytic functions, induces Interferon-gamma production, and promotes the development of Th1-type T cell responses. In murine models IL-12 has demonstrated antitumor , antimicrobial and antifungal activities. Because the mechanisms responsible for the antitumor activity of IL-12 are largely unknown, we explored the possibility that IL-12 may act as an inhibitor of angiogenesis. Tumor cells need to attract new vessels to grow locally and to induce distant metastasis, and a number of inhibitors of angiogenesis have antitumor activity. In the present studies we have shown that IL-12 is a potent inhibitor of angiogenesis in vivo. We have further shown that this effect is indirectly mediated through interferon gamma and, secondarily IP-10, a member of the alpha chemokine family that functions as a potent inhibitor of angiogenesis in vivo. By contrast, IL-15 potently stimulates neovascularization in vivo, acting directly on endothelial cells. IL-12 is presently being tested in initial clinical trials to assess its potential as a cancer therapeutic. Preclinical studies have documented that IL-12 can exert potent antitumor activity against a variery of experimental tumors, as well as anti-microbial and anti-fungal activity against a variety of infectious agents. Although IL-12 is known to exibit a variety of effects on the immune system that explain its anti-microbial functions, our understanding of its antitumor effects is conjectural. It would be very important to know how IL-12 is tumoricydal, and this information may be critical in designing product development. In particular, this information may help in predicting its toxicity. Our studies have confirmed i that IL-12 is an inhibitor of angiogenesis in vivo, and have further established that this activity is indirecly mediated through interferon-gamma and, secondarily, IP-10. In the course of these studies, we have developed improved biological tests for IL-12, established novel in vitro and in vivo models in which to study effects on angiogenesis.