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. 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.