The Role of IL-1β in the Early Tumor Cell-Induced Angiogenic Response
The Role of IL-1β in the Early Tumor Cell-Induced Angiogenic Response
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DOI：
10.4049/jimmunol.1202769
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发表时间：
2013-04-01
影响因子：
4.4
通讯作者：
Voronov, Elena
中科院分区：
文献类型：
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作者：
Carmi, Yaron;Dotan, Shahar;Voronov, Elena
在这项研究中，我们评估了IL-1 β参与恶性细胞诱导的早期血管生成反应，使用补充B16黑色素瘤细胞的基质胶塞。我们发现，在血管生成的反应，IL-1 β和血管内皮生长因子（VEGF）在一个新描述的自诱导电路，其中这些细胞因子中的每一个诱导其他相互作用。IL-1 β和VEGF通路通过骨髓来源的VEGF受体1（+）/IL-1 R1（+）未成熟髓样细胞和组织内皮细胞之间的相互作用发挥作用。骨髓细胞产生IL-1 β和其他促炎细胞因子，随后激活内皮细胞产生VEGF和其他促血管生成因子，并为血管生成和肿瘤进展提供炎症微环境。这些机制也观察到在非肿瘤早期血管生成反应引起的基质胶塞无论是rIL-1 β或重组VEGF。我们已经证明，IL-1 β抑制通过限制炎症和诱导未成熟骨髓细胞成熟为M1巨噬细胞来稳定地减少肿瘤生长。与此形成鲜明对比的是，VEGF中和后仅观察到肿瘤生长的短暂抑制，随后由反弹血管生成介导的肿瘤复发。这通过VEGF受体1（+）/IL-1 R1（+）细胞的重编程以表达缺氧诱导因子-1 α、VEGF和其他血管生成因子而发生，从而以旁分泌方式直接支持内皮细胞的增殖和血管形成。我们建议使用IL-1 β抑制作为一种有效的抗肿瘤治疗，目前正在优化其在临床应用的条件。免疫学杂志，2013，190：3500-3509。
In this study, we assessed the involvement of IL-1 beta in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1 beta and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1 beta and VEGF circuit acts through interactions between bone marrow-derived VEGF receptor 1(+)/IL-1R1(+) immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1 beta and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1 beta or recombinant VEGF. We have shown that IL-1 beta inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1(+)/IL-1R1(+) cells to express hypoxia inducible factor-1 alpha, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1 beta inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic. The Journal of Immunology, 2013, 190: 3500-3509.