Anti-adhesive effects of human soluble thrombomodulin and its domains
Anti-adhesive effects of human soluble thrombomodulin and its domains
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DOI：
10.1016/j.bbrc.2019.02.041
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发表时间：
2019-04-02
影响因子：
3.1
通讯作者：
Shimaoka, Motomu
中科院分区：
文献类型：
--
作者：
Kawamoto, Eiji;Nago, Nodoka;Shimaoka, Motomu
我们先前报道了白细胞β 2整合素（LFA-1和Mac-1）与血管内皮细胞（VEC）上表达的血栓调节蛋白（TM）的丝氨酸/苏氨酸丰富结构域结合。重组人可溶性TM（rhsTM，TMD 123）已被批准作为治疗感染性弥散性血管内凝血的药物。然而，TMD 123对白细胞整合素粘附于血管内皮细胞的作用尚不清楚。在目前的研究中，我们已经发现，整合素依赖性的结合之间的人外周血单核细胞（PBMC）和血管内皮细胞被抑制TMD 123。接下来，使用由分离的TM胞外结构域组成的突变蛋白，我们研究了负责TMD 123的抗粘附特性的结构特征。也就是说，我们研究了TM和白细胞结合的效果是否被施用TMD 123抑制。事实上，我们证实了TMD 123、TMD 1和TMD 3抑制PBMC与固定化重组蛋白TMD 123和TMD 3的结合。这些结果表明，TMD 123通过β 2整联蛋白和内皮TM抑制白细胞与内皮细胞的粘附。此外，由于TMD 1可能通过整合素以外的其他粘附受体与白细胞结合，因此TMD 1和TMD 3似乎通过不同的机制抑制白细胞与VEC上的TM结合。总之，TMD 123（rhsTM）、TMD 1或TMD 3是用于脓毒症的有希望的治疗选择，其减弱白细胞与VEC的整合素依赖性结合，并且可以抑制脓毒症中白细胞与VEC的不期望的粘附和迁移。(C)2019爱思唯尔公司All rights reserved.
We reported previously that leukocyte beta 2 integrins (LFA-1 and Mac-1) bind to the serine/threonine-rich domain of thrombomodulin (TM) expressed on vascular endothelial cells (VECs). Recombinant human soluble TM (rhsTM, TMD123) has been approved as a therapeutic drug for septic disseminated intravascular coagulation. However, the roles of TMD123 on the adhesion of leukocyte integrins to VECs remain unclear. In the current study, we have revealed that an integrin-dependent binding between human peripheral blood mononuclear cells (PBMCs) and VECs was inhibited by TMD123. Next, using mutant proteins composed of isolated TM extracellular domains, we examined the structural characteristics responsible for the anti-adhesion properties of TMD123. Namely, we investigated whether the effects of the binding of TM and leukocytes was inhibited by the administration of TMD123. In fact, we confirmed that TMD123, TMD1, and TMD3 inhibited the binding of PBMCs to the immobilized recombinant proteins TMD123 and TMD3. These results indicate that TMD123 inhibited the adhesion of leukocytes to endothelial cells via beta 2 integrins and endothelial TM. Moreover, since TMD1 might bind to leukocytes via other adhesion receptors than integrins, TMD1 and TMD3 appear to inhibit leukocyte binding to TM on VECs via different mechanisms. In summary, TMD123 (rhsTM), TMD1 or TMD3 is a promising treatment option for sepsis that attenuates integrin-dependent binding of leukocytes to VECs, and may inhibit the undesirable adhesion and migration of leukocytes to VECs in sepsis. (C) 2019 Elsevier Inc. All rights reserved.