Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI)α and TFPIβ.
Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI)α and TFPIβ.
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DOI：
10.1111/jth.12188
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Mast AE
中科院分区：
文献类型：
--
作者：
Maroney SA;Ellery PE;Wood JP;Ferrel JP;Martinez ND;Mast AE
组织因子途径抑制物（tissue factor pathway inhibitor，TFPI）是一种选择性剪接蛋白，具有两种异构体，TFPIα和TFPIβ，它们的羧基端结构和细胞定位不同。需要对其抑制活性进行详细表征，以确定组织因子（TF）介导的血栓形成和炎症性疾病中潜在的独特抑制作用，并了解靶向TFPI亚型不同结构区域的药物如何改变血友病患者的止血。使用体外和体内试验比较了定位于CHO细胞表面的TFPIβ与可溶性TFPIα的TF抑制活性。在TF-FVIIa介导的FXa生成试验中，TFPIβ是比TFPIα略好的抑制剂，TFPI α比TFPI- 160（一种与TFPIβ相似的TFPI可溶性改变形式）好约3倍。在直接FXA抑制试验中，TFPIβ的IC 50比TFPIα低2.5倍，比TFPI-160低56倍。TFPIβ通过Matrigel抑制TF介导的CHO细胞迁移，而TFPIα或TFPI-160是较差的抑制剂，表明TFPIβ在细胞迁移期间有效地阻断TF引发的信号传导事件，该细胞迁移通过可溶形式的TFPI不可渗透的基质。此外，TFPIβ在尾静脉注射到SCID小鼠中后抑制TF依赖性CHO细胞浸润到肺组织中，并阻断消耗性凝血病的发展。当与TFPIα相比时，TFPIβ是TF促凝血活性的稍微更好的抑制剂。作为一种表面结合蛋白，TFPIβ是比可溶性TFPIα更好的TF介导的细胞迁移的抑制剂，并且可能在炎症内皮细胞和/或单核细胞上明显抑制TF介导的信号传导事件。
Tissue factor pathway inhibitor (TFPI) is an alternatively spliced protein with two isoforms, TFPIα and TFPIβ, which differ in their carboxy-terminal structure and cellular localization. Detailed characterization of their inhibitory activity is needed to define potentially unique inhibitory roles in tissue factor (TF) mediated thrombotic and inflammatory disease and to understand how pharmaceuticals targeted to different structural regions of the TFPI isoforms alter hemostasis in hemophilia patients. The TF inhibitory activity of TFPIβ localized to the surface of CHO cells was compared to soluble TFPIα using in vitro and in vivo assays. In TF-FVIIa-mediated FXa generation assays, TFPIβ was a slightly better inhibitor than TFPIα, which was ~3-fold better than TFPI- 160, a soluble, altered form of TFPI similar to TFPIβ. In direct FXa inhibitory assays, TFPIβ had an IC50 2.5-fold lower than TFPIα and 56-fold lower than TFPI-160. TFPIβ inhibited TF-mediated CHO cell migration though Matrigel, while TFPIα or TFPI-160 were poor inhibitors, demonstrating that TFPIβ effectively blocks TF-initiated signaling events during cellular migration through matrices not permeable to soluble forms of TFPI. Further, TFPIβ inhibited TF-dependent CHO cell infiltration into lung tissue following tail vein injection into SCID mice and blocked development of consumptive coagulopathy. When compared to TFPIα, TFPIβ is a slightly better inhibitor of TF procoagulant activity. As a surface associated protein, TFPIβ is a much better inhibitor of TF-mediated cellular migration than soluble TFPIα and may distinctly act in the inhibition of TF-mediated signaling events on inflamed endothelium and/or monocytes.
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