Inflammation and coagulation are two important processes implicated in venous thromboembolism (VTE). 15-epi-lipoxin A4 (15-epi-LXA4) is the epimer of LXA4, a small lipid molecule, is known to play a key role in the resolution of inflammation. This study aimed to demonstrate whether 15-epi-LXA4 could suppress the inflammatory factor tumor necrosis factor-alpha (TNF-α)-induced upregulation of tissue factor (TF), an important regulator of the blood coagulation cascade, and evaluated the possible underlying mechanisms. We found that 15-epi-LXA4 not only reduced the up-regulation of mRNA and antigens, but also lowered the activity of TF (elevated by TNF-α) in primary culture of human umbilical vein endothelial cells (pc-HUVECs). In addition, 15-epi-LXA4 suppressed the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, induced by TNF-α, in pc-HUVECs. 15-epi-LXA4 also inhibited the binding of NF-κB on the TF promoter, which is otherwise enhanced by TNF-α. The role of 15-epi-LXA4 in regulating TNF-α-induced effects was enhanced by the PI3K inhibitor and prevented by the PI3K activator. In conclusion, 15-epi-LXA4 lowered the TNF-α-induced high TF expression and activity by suppressing PI3K/AKT signaling activation, thereby reducing the binding capacity of NF-κB on the TF promoter in pc-HUVECs.

中文翻译：

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15-表脂蛋白A4通过PI3K / AKT /NF-κB轴抑制人脐静脉内皮细胞中TNF-α诱导的组织因子表达。

炎症和凝血是涉及静脉血栓栓塞（VTE）的两个重要过程。15-epi-lipoxin A4（15-epi-LXA4）是LXA4（一种小脂质分子）的差向异构体，已知在炎症消退中起关键作用。这项研究旨在证明15-epi-LXA4是否可以抑制炎症因子肿瘤坏死因子-α（TNF-α）诱导的组织因子（TF）的上调，该因子是凝血级联反应的重要调节剂，并评估了可能的潜在机制机制。我们发现15-epi-LXA4不仅减少了mRNA和抗原的上调，而且还降低了人脐静脉内皮细胞（pc-HUVECs）原代培养中TF的活性（TNF-α升高）。此外，15-epi-LXA4抑制了磷酸肌醇3激酶（PI3K）/ AKT信号通路的激活，在pc-HUVEC中由TNF-α诱导。15-epi-LXA4还抑制NF-κB在TF启动子上的结合，否则可通过TNF-α增强。PI3K抑制剂增强了15-epi-LXA4在调节TNF-α诱导的作用中的作用，而PI3K激活剂则阻止了该作用。总之，15-epi-LXA4通过抑制PI3K / AKT信号激活降低了TNF-α诱导的高TF表达和活性，从而降低了pc-HUVEC中TF启动子上的NF-κB的结合能力。