Antiangiogenic and antitumor activities of IL-27
Antiangiogenic and antitumor activities of IL-27
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DOI：
10.4049/jimmunol.176.12.7317
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发表时间：
2006-06-15
影响因子：
4.4
通讯作者：
Yoshimoto, Takayuki
中科院分区：
文献类型：
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作者：
Shimizu, Motomu;Shimamura, Mariko;Yoshimoto, Takayuki
IL-27是一种新的IL-6/IL-12家族细胞因子，在Th1应答的早期调控中发挥重要作用。我们最近证明IL-27对高免疫原性小鼠结肠癌具有强大的抗肿瘤活性，其主要通过CD8(+) T细胞介导。在这项研究中，我们进一步评估了IL-27的抗肿瘤和抗血管生成活性，使用免疫原性较差的小鼠黑色素瘤B16F10肿瘤，设计成过表达单链IL-27 （B16F10 + IL-27）。B16F10 + IL-27细胞不仅对sc肿瘤有抗肿瘤活性，而且对实验性肺转移也有抗肿瘤活性。在ifn - γ敲除小鼠中也观察到类似的IL-27抗肿瘤和抗转移活性。在NOD-SCID小鼠中，这些活性有所下降，但仍保持得相当好，这表明除了免疫反应之外，这些活性的发挥也涉及不同的机制。抗血管内皮生长因子和CD31抗体的免疫组化分析显示，B16F10 + IL-27细胞显著抑制肿瘤诱导的肺转移瘤新生血管形成。此外，B16F10 + IL-27细胞通过背囊法明显抑制血管生成，IL-27对鸡胚绒毛尿囊膜血管生成的抑制作用呈剂量依赖性。IL-27直接作用于HUVECs，诱导产生抗血管生成趋化因子、ifn - γ诱导蛋白（IP-10）和ifn - γ诱导的单因子。最后，在sc . B16F10 + IL-27肿瘤部位检测到ifn - γ诱导的IP-10和单因子mRNA表达增强，且IL-27的抗肿瘤活性部分被抗IP-10抑制。提示IL-27具有较强的抗血管生成活性，在其抗肿瘤和抗转移活性中发挥重要作用。
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.