Ristimäki A, Narko K, Enholm B, Joukov V, Alitalo K
Department of Bacteriology and Immunology, the Haartman Institute, and the Department of Obstetrics and Gynecology, Haartmaninkatu 2, FIN-00290 University of Helsinki, Helsinki, Finland.
J Biol Chem. 1998 Apr 3;273(14):8413-8. doi: 10.1074/jbc.273.14.8413.
Vascular endothelial growth factor (VEGF) is a prime regulator of normal and pathological angiogenesis. Three related endothelial cell growth factors, VEGF-B, VEGF-C, and VEGF-D were recently cloned. We have here studied the regulation of VEGF-C, a lymphatic endothelial growth factor, by angiogenic proinflammatory cytokines. Interleukin (IL)-1beta induced a concentration- and a time-dependent increase in VEGF-C, but not in VEGF-B, mRNA steady-state levels in human lung fibroblasts. The increase in VEGF-C mRNA levels was mainly due to increased transcription rather than elevated mRNA stability as detected by the nuclear run-on method and by following mRNA decay in the presence of an inhibitor of transcription, respectively. In contrast, angiopoietin-1 mRNA, encoding the ligand for the endothelial-specific Tek/Tie-2 receptor, was down-regulated by IL-1beta. Tumor necrosis factor-alpha and IL-1alpha also elevated VEGF-C mRNA steady-state levels, whereas the IL-1 receptor antagonist and dexamethasone inhibited the effect of IL-1beta. Experiments with cycloheximide indicated that the effect of IL-1beta was independent of protein synthesis. Hypoxia, which is an important inducer of VEGF expression, had no effect on VEGF-B or VEGF-C mRNA levels. IL-1beta and tumor necrosis factor-alpha also stimulated the production of VEGF-C protein by the fibroblasts. Cytokines and growth factors have previously been shown to down-regulate VEGF receptors in vascular endothelial cells. We found that the mRNA for the VEGF- and VEGF-C-binding VEGFR-2 (KDR/Flk-1) was stimulated by IL-1beta in human umbilical vein endothelial cells, whereas the mRNA levels of VEGFR-1 (Flt-1) and VEGFR-3 (Flt-4) were not altered. Our data suggest that in addition to VEGF, VEGF-C may also serve as an endothelial stimulus at sites of cytokine activation. In particular, these results raise the possibility that certain proinflammatory cytokines regulate the lymphatic vessels indirectly via VEGF-C.
血管内皮生长因子（VEGF）是正常和病理性血管生成的主要调节因子。最近克隆出了三种相关的内皮细胞生长因子，即VEGF-B、VEGF-C和VEGF-D。我们在此研究了促血管生成的促炎细胞因子对淋巴管内皮生长因子VEGF-C的调节作用。白细胞介素（IL）-1β在人肺成纤维细胞中诱导VEGF-C的mRNA稳态水平呈浓度和时间依赖性增加，但对VEGF-B无此作用。VEGF-C mRNA水平的增加主要是由于转录增加，而非mRNA稳定性升高，这分别通过核转录分析方法以及在存在转录抑制剂的情况下跟踪mRNA降解得以检测。相反，编码内皮特异性Tek/Tie-2受体配体的血管生成素-1 mRNA被IL-1β下调。肿瘤坏死因子-α和IL-1α也升高了VEGF-C mRNA的稳态水平，而IL-1受体拮抗剂和地塞米松抑制了IL-1β的作用。用放线菌酮进行的实验表明，IL-1β的作用不依赖于蛋白质合成。缺氧是VEGF表达的重要诱导因素，但对VEGF-B或VEGF-C mRNA水平无影响。IL-1β和肿瘤坏死因子-α也刺激成纤维细胞产生VEGF-C蛋白。细胞因子和生长因子此前已被证明可下调血管内皮细胞中的VEGF受体。我们发现，在人脐静脉内皮细胞中，IL-1β刺激了结合VEGF和VEGF-C的VEGFR-2（KDR/Flk-1）的mRNA表达，而VEGFR-1（Flt-1）和VEGFR-3（Flt-4）的mRNA水平未发生改变。我们的数据表明除VEGF外，VEGF-C在细胞因子激活部位也可能作为一种内皮刺激因子。特别是，这些结果增加了某些促炎细胞因子通过VEGF-C间接调节淋巴管的可能性。
