Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12.
Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12.
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发表时间：
2000-02
期刊：
影响因子：
11.2
通讯作者：
D. Duda;M. Sunamura;Lucian Lozonschi;T. Kodama;Shinichi Egawa;Gaku Matsumoto;H. Shimamura;K. Shibuya;Kazunori Takeda;Seiki Matsuno
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文献类型：
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作者：
D. Duda;M. Sunamura;Lucian Lozonschi;T. Kodama;Shinichi Egawa;Gaku Matsumoto;H. Shimamura;K. Shibuya;Kazunori Takeda;Seiki Matsuno
白细胞介素-12（IL-12）作为一种抗肿瘤剂，已被发现是免疫应答的关键调节剂，特别是涉及CTL和自然杀伤（NK）细胞的免疫应答。我们在此报告IL-12对NK细胞耗竭的严重联合免疫缺陷小鼠中的人类以及小鼠肿瘤的抗血管生成作用，使用经基因工程改造以分泌这种细胞因子的成纤维细胞。虽然肿瘤细胞的体外生长不受IL-12的存在，IL-12分泌成纤维细胞的共同接种强烈抑制免疫缺陷小鼠的肿瘤生长。在植入IL-12分泌成纤维细胞的区域中，肿瘤周围的新血管形成被显著抑制，导致肿瘤生长受到抑制。肿瘤样本切片中的凝集素染色也显示血管数量显着减少。IFN-γ及其诱导型抗血管生成趋化因子IFN-γ诱导蛋白10的RNA表达在用IL-12培养的内皮细胞中被刺激。同时发现IL-12下调内皮细胞有丝分裂原血管内皮生长因子和碱性成纤维细胞生长因子的表达。IL-12的抗肿瘤作用伴随着有趣的组织学变化，包括高度的角化和细胞凋亡以及人肿瘤增殖率的降低和小鼠肿瘤的广泛坏死。
As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.