Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI).
Thrombin-activatable procarboxypeptidase B (proCPB or thrombin-activatable fibrinolysis inhibitor or TAFI) is a plasma procarboxypeptidase that is activated by the thrombin-thrombomodulin complex on the vascular endothelial surface. The activated CPB removes the newly exposed carboxyl terminal lysines in the partially digested fibrin clot, diminishes tissue plasminogen activator and plasminogen binding, and protects the clot from premature lysis. We have recently shown that CPB is catalytically more efficient than plasma CPN, the major plasma anaphylatoxin inhibitor, in inhibiting bradykinin, activated complement C3a, C5a, and thrombin-cleaved osteopontin in vitro. Using a thrombin mutant (E229K) that has minimal procoagulant properties but retains the ability to activate protein C and proCPB in vivo, we showed that infusion of E229K thrombin into wild-type mice reduced bradykinin-induced hypotension but it had no effect in proCPB-deficient mice, indicating that the beneficial effect of E229K thrombin is mediated through its activation of proCPB and not protein C. Similarly proCPB-deficient mice displayed enhanced pulmonary inflammation in a C5a-induced alveolitis model and E229K thrombin ameliorated the magnitude of alveolitis in wild-type but not proCPB-deficient mice. ProCPB-deficient mice also displayed enhanced arthritis in an inflammatory arthritis model. Thus, our in vitro and in vivo data support the thesis that thrombin-activatable CPB has broad anti-inflammatory properties. By specific cleavage of the carboxyl terminal arginines from C3a, C5a, bradykinin and thrombin-cleaved osteopontin, it inactivates these active inflammatory mediators. Along with the activation of protein C, the activation of proCPB by the endothelial thrombin-thrombomodulin complex represents a homeostatic feedback mechanism in regulating thrombin's pro-inflammatory functions in vivo.
Leung
Lawrence L K
LL
Department of Medicine, Stanford University School of Medicine and Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA. lawrence.leung@stanford.edu
Myles
Timothy
T
Nishimura
Toshihiko
T
Song
Jason J
JJ
Robinson
William H
WH
D000818:Animals; D043424:Carboxypeptidase B / Q000378:metabolism / Q000494:pharmacology*; D025901:Carboxypeptidase B2 / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation; D051379:Mice; D018448:Models, Immunological; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D018180:Thrombomodulin / Q000737:chemistry / Q000378:metabolism
D018180:Thrombomodulin; D043424:Carboxypeptidase B; D025901:Carboxypeptidase B2; D013917:Thrombin