Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide primed mice
Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide primed mice
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DOI：
10.4049/jimmunol.173.7.4669
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Okada, N
中科院分区：
文献类型：
--
作者：
Asai, S;Sato, T;Okada, N
羧基肽酶R （CPR）是除了稳定的羧基肽酶n外，还存在于血清中的一种热不稳定酶。它从炎症肽如补体C3a和C5a、缓激肽和脑啡肽中切割c端碱性氨基酸、精氨酸和赖氨酸。这种酶是由原羧肽酶R （proCPR）产生的，也被称为凝血酶活化纤维蛋白溶解抑制剂，在凝血酶、纤溶酶和胰蛋白酶等蛋白水解酶裂解后产生。我们通过敲除proCPR基因的外显子4和5来产生proCPR缺陷小鼠，这被认为是CPR功能所必需的。在LPS刺激下，proCPR（+/+）、proCPR（+/-）和proCPR（-/-）小鼠的致死率几乎没有差异。然而，可以激活和消耗体内几乎所有补体的眼镜蛇毒因子的挑战，在LPS致敏后，对proCPR（-/-）小鼠诱导了致死效应，从而上调了C5a受体的表达。相比之下，proCPR（+/+）和proCPR（+/-）小鼠能够耐受有限剂量（30 U）的眼镜蛇毒因子攻击。虽然在体内，羧肽酶N在炎症肽的失活中起作用，但CPR在调节高炎症中也可能起重要作用。
Carboxypeptidase R (CPR) is a heat-labile enzyme found in serum in addition to stable carboxypeptidase N. CPR cleaves the C-terminal basic amino acids, arginine and lysine, from inflammatory peptides such as complement C3a and C5a, bradykinin, and enkephalin. This enzyme is generated from procarboxypeptidase R (proCPR), also known as thrombin-activatable fibrinolysis inhibitor, following cleavage by proteolytic enzymes such as thrombin, plasmin, and trypsin. We generated proCPR-deficient mice by knocking out exons 4 and 5 of the proCPR gene, which are regarded as essential for CPR function. At LPS challenge, there was virtually no difference in lethality among proCPR(+/+), proCPR(+/-), and proCPR(-/-) mice. However, challenge with cobra venom factor, which can activate and deplete almost all complement in vivo, induced a lethal effect on proCPR(-/-) mice following LPS sensitization which up-regulates C5a receptor expression. In contrast, proCPR(+/+) and proCPR(+/-) mice were able to tolerate the cobra venom factor challenge with the limited dose (30 U). Although carboxypeptidase N plays a role in inactivation of inflammatory peptides in vivo, CPR may also be important in the regulation of hyperinflammation.