Procarboxypeptidase R Deficiency Causes Increased Lethality in Concanavalin A-Induced Hepatitis in Female Mice

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. Basic carboxypeptidases (CPs) are present in plasma and cleave C-terminal arginine and lysine residues from various peptides including inflammatory mediators1-4). Carboxypeptidase N (CPN) is present in an active form in plasma, whereas carboxypeptidase R (CPR) exists in a precursor form (procarboxypeptidase R (proCPR)).