Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide-primed mice.
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.
Asai
Suzuka
S
Department of Biodefense, Graduate School of Medical Sciences, Nagoya City University, Japan.
Sato
Tomoo
T
Tada
Toyohiro
T
Miyamoto
Tomomi
T
Kimbara
Noriaki
N
Motoyama
Noboru
N
Okada
Hidechika
H
Okada
Noriko
N
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
D004792:Enzyme Precursors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003165:Complement System Proteins; D025901:Carboxypeptidase B2