title: Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide-primed mice.
abstract: 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.
authors.affiliation: Department of Biodefense, Graduate School of Medical Sciences, Nagoya City University, Japan.
authors.forename: Suzuka
authors.initials: S
authors.lastname: Asai
authors.forename: Tomoo
authors.initials: T
authors.lastname: Sato
authors.forename: Toyohiro
authors.initials: T
authors.lastname: Tada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kimbara
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
mesh_terms: D000818:Animals; D025901:Carboxypeptidase B2 / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D003165:Complement System Proteins / Q000502:physiology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D004792:Enzyme Precursors / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006168:Guinea Pigs; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000401:mortality*; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044967:Serum / Q000201:enzymology; D012772:Shock, Septic / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D012867:Skin / Q000201:enzymology / Q000473:pathology
chemical_list: D004792:Enzyme Precursors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003165:Complement System Proteins; D025901:Carboxypeptidase B2