Procarboxypeptidase R Deficiency Causes Increased Lethality in Concanavalin A-Induced Hepatitis in Female Mice
Procarboxypeptidase R Deficiency Causes Increased Lethality in Concanavalin A-Induced Hepatitis in Female Mice
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DOI：
10.1248/bpb.33.1256
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发表时间：
2010-07-01
影响因子：
2
通讯作者：
Okada, Noriko
中科院分区：
文献类型：
--
作者：
Asai, Suzuka;Kimbara, Noriaki;Okada, Noriko
羧肽酶R（CPR），也称为凝血酶激活的纤维蛋白溶解抑制剂（TAFI），是通过其酶原（proCPR）的蛋白水解裂解产生的酶。CPR从炎性肽如C3 a和C5 a、缓激肽、脑啡肽和凝血酶裂解的N-末端片段骨桥蛋白（裂解的N-OPN）中去除C-末端精氨酸。在伴刀豆球蛋白A（ConA）诱导的免疫介导的暴发性肝炎小鼠模型中，裂解的N-OPN是诱导趋化因子或细胞因子产生的重要肽之一。在目前使用proCPR缺陷小鼠的研究中，我们表明，将Con A注射到小鼠尾静脉中可以在proCPR缺陷雌性小鼠中诱导显著更高的致死率，但在雄性小鼠中则不然。此外，CPR活性的缺乏增加血清巨噬细胞炎性蛋白-2（MIP-2）和高迁移率族蛋白1（HMGB 1）水平后，刀豆蛋白A注射。这些体内研究结果表明，CPR有助于防止Con A诱导的肝炎。
Carboxypeptidase R (CPR), also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is an enzyme generated by proteolytic cleavage of its zymogen (proCPR). CPR removes the C-terminal arginine from inflammatory peptides such as C3a and C5a, bradykinin, enkephalin, and the thrombin-cleaved N-terminal fragment osteopontin (cleaved N-OPN). In the mouse model of concanavalin A (Con A)-induced immune-mediated fulminating hepatitis, cleaved N-OPN is one of the important peptides that induce the production of chemokines or cytokines. In the current study using proCPR deficient mice, we showed that injection of Con A into the mouse tail vein can induce a significantly higher lethality in proCPR-deficient female but not in male mice. Furthermore, a lack of CPR activity increased serum macrophage inflammatory protein-2 (MIP-2) and high-mobility group box 1 (HMGB1) levels after Con A injection. These in vivo findings suggest that CPR helps to protect against Con A-induced hepatitis.