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Molecular mechanism of growth factor receptor expression in human microvascular endothelial cells.

人微血管内皮细胞生长因子受体表达的分子机制。

基本信息

批准号：
06836014
负责人：
ONO Mayumi
金额：
$ 1.34万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Oxygen radicals are generated under various pathologic condition including inflammation, ischemia reperfusion, sepsis and ultraviolet light irradiation, The vascular endothelium is one of the prime targets for oxidant injury in a variety of inflammatory conditions. It is reported that hypoxic or hyperoxic stress induces angiogenic signaling in human glioma cells. Among angiogenic factors, we especially focused on the mechanism of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) induction under various stress.1) The expression of VEGF has been implicated in brain tumor angiogenesis and the promoter region for VEGF gene conditions several SP-1 and AP-1 (c-fos/c-jun) binding motifs. Among 8 human glioma cell lines, cellular mRNA levels of transcription factors, SP-1 and AP-1 (c-fos/c-jun), were found to be closely correlated with those of VEGF.Our data indicate that VEGF gene expression by bFGF or TNF-alpha is mediated in part through the transcription factor SP-1, and that by hypoxia is mediated through the transcription factor AP-1.2) Another angiogeic factor is the cytokine, IL-8, that is produced at high levels in monocytes, macrophages and also human brain tumors. IL-8 induces cell migration of human umbilical endothelial cells, angiogenesis in rat cornea and tubular morphogenesis by microvascular endothelilal cells. Recent studies demonstrate that the IL-8 gene promoter region contains binding sites for AP-1 and NFxB.Moreover, co-administration of anti-IL-8 antibody inhibited tubular morphogenesis enhanced by H_2O_2, and IL-8 itself also enhanced formation of tube-like structures. H_2O_2 increased production of IL-8 in endothelial cells. Treatment with antisense NFkB oligonucleotide completely blcked the H_2O_2-dependent IL-8 production. Transcription factors SP-1, AP-1 and NFxB appeared to be involved in VEGF or IL-8 induction in glioma cells under various stress.

氧自由基在炎症、缺血再灌注、败血症和紫外线照射等多种病理条件下产生，血管内皮是多种炎症条件下氧化损伤的主要靶标之一。据报道，缺氧或高氧应激会诱导人神经胶质瘤细胞中的血管生成信号传导。在血管生成因子中，我们特别关注各种应激下血管内皮生长因子（VEGF）和白细胞介素8（IL-8）诱导的机制。1）VEGF的表达与脑肿瘤血管生成有关，并且VEGF基因的启动子区域调节多个SP-1和AP-1（c-fos/c-jun）结合基序。在 8 种人胶质瘤细胞系中，转录因子 SP-1 和 AP-1 (c-fos/c-jun) 的细胞 mRNA 水平被发现与 VEGF 的 mRNA 水平密切相关。我们的数据表明，bFGF 或 TNF-α 的 VEGF 基因表达部分通过转录因子 SP-1 介导，而缺氧则通过转录因子 AP-1.2 介导。细胞因子 IL-8，在单核细胞、巨噬细胞以及人脑肿瘤中产生高水平。 IL-8 诱导人脐带内皮细胞的细胞迁移、大鼠角膜中的血管生成以及微血管内皮细胞的管状形态发生。最近的研究表明IL-8基因启动子区含有AP-1和NFxB的结合位点。此外，抗IL-8抗体的共同给药抑制了H_2O_2增强的管状形态发生，并且IL-8本身也增强了管状结构的形成。 H_2O_2 增加内皮细胞中 IL-8 的产生。用反义 NFkB 寡核苷酸处理完全阻止了 H_2O_2 依赖性 IL-8 的产生。转录因子 SP-1、AP-1 和 NFxB 似乎参与了神经胶质瘤细胞在各种应激下的 VEGF 或 IL-8 诱导。