Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, Kuwano M
Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
Mol Cell Biol. 1997 Jul;17(7):4015-23. doi: 10.1128/MCB.17.7.4015.
Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms.
肿瘤坏死因子α（TNF-α）是一种由巨噬细胞/单核细胞产生的多肽，它可调节血管内皮细胞中多种基因的表达并诱导血管生成。然而，TNF-α介导血管生成的潜在机制尚未完全明确。在本研究中，我们评估了TNF-α诱导的血管生成是通过TNF-α自身介导，还是通过其他TNF-α诱导的血管生成促进因子间接介导。用TNF-α（100 U/ml）处理人微血管内皮细胞后，白细胞介素-8（IL-8）、血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）及其受体的细胞mRNA水平升高。抗IL-8、抗VEGF和抗bFGF抗体的施用抑制了血管内皮细胞中TNF-α依赖性的管状形态发生，同时施用这三种抗体几乎完全消除了管状结构的形成。此外，用Sp1、NF-κB和c-Jun反义寡核苷酸处理可抑制微血管内皮细胞的TNF-α依赖性管状形态发生。施用NF-κB反义寡核苷酸几乎完全抑制了TNF-α依赖性的IL-8产生，并部分消除了TNF-α依赖性的VEGF产生，而Sp1反义序列部分抑制了TNF-α依赖性的VEGF产生。c-Jun反义寡核苷酸显著抑制了TNF-α依赖性的bFGF产生，但不影响IL-8和VEGF的产生。施用抗IL-8或抗VEGF抗体也可在体内阻断TNF-α诱导的兔角膜新生血管形成。因此，TNF-α诱导的血管生成似乎在体外和体内均通过多种血管生成因子进行调节，并且该途径通过旁分泌和/或自分泌机制进行控制。
