TRANSCRIPTIONAL REGULATION OF TISSUE FACTOR EXPRESSION IN HUMAN ENDOTHELIAL-CELLS
TRANSCRIPTIONAL REGULATION OF TISSUE FACTOR EXPRESSION IN HUMAN ENDOTHELIAL-CELLS
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DOI：
10.1161/01.atv.15.5.612
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发表时间：
1995-05-01
影响因子：
8.7
通讯作者：
MACKMAN, N
中科院分区：
文献类型：
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作者：
PARRY, GCN;MACKMAN, N
血管内皮细胞的组织因子(TF)表达与多种临床疾病患者的血栓形成有关。在致命脓毒症的狒狒模型中，转铁蛋白由脾微血管内皮细胞表达。在体外，内皮细胞在肿瘤坏死因子-α(TNF-α)、白介素1-β(IL-1β)和细菌内毒素(内毒素[LPS])的刺激下表达转铁蛋白。在这里，我们确定了在原代人内皮细胞中控制TF基因转录的顺式作用调控元件。功能研究表明，Tf启动子含有一个56个碱基的增强子(-227~-172个碱基)，含有两个激活蛋白-1(AP-1)位点和一个类似kappa B的位点，介导了肿瘤坏死因子-α、白介素1-β和内毒素的诱导。电泳迁移率改变分析表明，内皮细胞具有结构性AP-1结合活性，而kappa B样位点5‘-CGGAGTITTCC-3’结合由c-Rel-P65杂二聚体组成的可诱导核复合体。综上所述，我们的数据表明，内皮细胞中TF基因转录的诱导是由Fos-Jun和c-Rel-P65异源二聚体之间的功能相互作用所介导的。
Tissue factor (TF) expression by endothelial cells is implicated in thrombotic episodes in patients with a variety of clinical disorders. In a baboon model of lethal sepsis, TF is expressed by endothelial cells in the splenic microvasculature. In vitro, endothelial cells are induced to express TF in response to tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and bacterial endotoxin (lipopolysaccharide [LPS]). Here, we identified cis-acting regulatory elements that control TF gene transcription in primary human endothelial cells. Functional studies showed that the TF promoter contained a 56-bp enhancer (-227 to -172 bp), which included two activator protein-1 (AP-1) sites and a kappa B-like site, that mediated induction by TNF-alpha, IL-1 beta, and LPS. Electrophoretic mobility shift assays demonstrated that endothelial cells contained constitutive AP-1 binding activity, whereas the kappa B-like site, 5'-CGGAGTITTCC-3', bound an inducible nuclear complex composed of c-Rel-p65 heterodimers. Taken together, our data suggest that induction of TF gene transcription in endothelial cells is mediated by functional interactions between Fos-Jun and c-Rel-p65 heterodimers.