The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis
The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis
复制标题
DOI：
10.1215/s1152851704001061
复制
发表时间：
2005-04-01
期刊：
影响因子：
15.9
通讯作者：
Van Meir, EG
中科院分区：
文献类型：
--
作者：
Brat, DJ;Bellail, AC;Van Meir, EG
白介素 8（IL-8 或 CXCL8）是一种具有 CXC 氨基酸基序的趋化因子，最初以其白细胞趋化活性为特征，现在已知它也具有致瘤和促血管生成的特性。在人类神经胶质瘤中，IL-8 在体外和体内均以高水平表达和分泌，最近的实验表明它对于神经胶质瘤的新生血管形成和进展至关重要。 IL-8 水平与胶质瘤的组织学分级相关，最恶性的胶质母细胞瘤在坏死周围的假栅栏细胞中表达最高，表明缺氧/缺氧可能会刺激表达。除了缺氧/缺氧刺激外，神经胶质瘤中 IL-8 的增加还因 Fas 连接、死亡受体激活、胞质 Ca2+、TNF-α、IL-1 和其他细胞因子和各种细胞应激而发生。 IL-8 启动子包含转录因子 NF-kappa B、AP-1 和 C-EBP/NF-IL-6 等的结合位点。 AP-1 已被证明可通过神经胶质瘤中的缺氧介导 IL-8 上调。潜在的肿瘤抑制因子 ING4 最近被证明是神经胶质瘤中 NF-κ B 介导的 IL-8 转录和随后血管生成的关键调节因子。可能有助于 IL-8 介导的肿瘤发生和血管生成反应的 IL-8 受体包括 CXCR1 和 CXCR2，两者都是 G 蛋白偶联，以及细胞因子的 Duffy 抗原受体，其没有明确的细胞内信号传导能力。 IL-8 的促血管生成活性主要发生在与 CXCR2 结合后，但 CXCR1 似乎也通过独立的 stri1-GTPase 活性发挥作用。 IL-8 发挥促血管生成功能的机制的精确定义需要进一步研究，以开发有效的 IL-8 靶向疗法。
Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation,, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca2+, TNF-alpha, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-kappa B, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappa B-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, striall-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.