A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development
A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development
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DOI：
10.1096/fj.03-0483fje
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Cohen, S
中科院分区：
文献类型：
--
作者：
Bar, D;Apte, RN;Cohen, S
白细胞介素-1（IL-1）参与炎症、肿瘤生长和转移，使其成为治疗干预的有吸引力的靶点。在这里，我们表明，一个低的，但稳态水平的天然存在的IL-1受体拮抗剂（IL-1Ra）的连续交付减少炎症反应和抑制小鼠肿瘤的发展，这是由IL-1，主要是分泌型IL-1 β诱导的现象。IL-IRa由微囊化的基因工程细胞递送，所述细胞过表达并分泌该介体。对于肿瘤模型，我们使用纤维肉瘤细胞系，其分泌高水平的IL-1 β;当皮下注射时，在小鼠中，这些细胞发展成以非常活跃的血管生成模式为特征的大肿瘤。IL-1 β的促血管生成特征在低水平的细胞因子下表现出来，并且需要每天释放25 ng的IL-IRa来对抗其作用并抑制肿瘤发展。IL-IRa的连续递送有助于改善微囊化细胞系统的生物相容性;系统周围的纤维化囊薄得多，毛细血管和炎性细胞显著减少。我们的研究结果不仅指出了IL-1Ra在炎症和肿瘤生长中的抗血管生成特性，而且还为治疗涉及IL-1的疾病提供了更有效和更方便的方法。
The involvement of interleukin-1 (IL-1) in inflammation, tumor growth, and metastasis makes it an attractive target for therapeutic intervention. Here, we show that a continuous delivery of a low, but steady-state level of the naturally occurring IL-I receptor antagonist (IL-IRa) reduced inflammatory responses and inhibited tumor development in mice, phenomena that are induced by IL-1, mainly secretable IL-1 beta. The IL-IRa was delivered from microencapsulated genetically engineered cells, which overexpress and secrete this mediator. For a tumor model, we used fibrosarcoma cell line, which secretes high levels of IL-1 beta; when injected s.c. into mice, the cells developed into large tumors characterized by very active angiogenic patterns. The proangiogenic features of IL-1 beta were manifested at low levels of the cytokine, and release of 25 ng per day of the IL-IRa was needed to oppose its effects and inhibit tumor development. The continuous delivery of the IL-IRa contributed to improved biocompatibility of the microencapsulated cell systems; the fibrotic sac surrounding the systems was much thinner with significantly less blood capillaries and inflammatory cells. Not only do our findings point to the antiangiogenic properties of IL-1Ra in inflammation and tumor growth, but they also provide a more efficient and convenient way for treating diseases involving IL- 1.