TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2
TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2
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DOI：
10.1002/eji.201445070
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发表时间：
2015-02-01
影响因子：
5.4
通讯作者：
Wouters, Diana
中科院分区：
文献类型：
--
作者：
Keizer, Mischa P.;Pouw, Richard B.;Wouters, Diana
补体的凝集素途径（LP）具有抵抗入侵病原体的保护功能。最近的研究还表明，LP在缺血/再灌注（I/R）损伤中发挥着重要作用。MBL相关的丝氨酸蛋白酶（MASP）-2似乎在这个过程中是至关重要的。丝氨酸蛋白酶抑制剂Cl-抑制剂是MASP-2的主要抑制剂。此外，抑肽酶，一种Kunitz型抑制剂，显示在体外抑制MASP-2活性。在这项研究中，我们研究了Kunitz型抑制剂组织因子途径抑制剂（TFPI）是否也能够抑制MASP-2。通过甘露聚糖包被的板上的C4沉积诱导并检测离体LP。在液相显色测定中测量MASP-2活性。在不存在或存在特异性单克隆抗体的情况下，使用rTFPI来研究哪些TFPI结构域有助于MASP-2抑制。在这里，我们确定TFPI作为MASP-2的新型选择性抑制剂，而不影响MASP-1或经典途径蛋白酶C1 s和C1 r。TFPI的Kunitz-2结构域是抑制MASP-2所需的。考虑到MASP-2在补体介导的I/R损伤中的作用，TFPI对该蛋白酶的抑制可能是限制诸如脑中风、心肌梗塞或实体器官移植等病症中的组织损伤的令人感兴趣的治疗方法。
The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.