Regulation of Tissue Inflammation by Thrombin-Activatable Carboxypeptidase B (or TAFI)

Abstract

Thrombin-activatable procarboxypeptidase B (proCPB or thrombin-activatable fibrinolysis inhibitor or TAFI) is a plasma procarboxypeptidase that is activated by the thrombinthrombomodulin 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 thrombincleaved 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 antiinflammatory 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 thrombinthrombomodulin complex represents a homeostatic feedback mechanism in regulating thrombin's pro-inflammatory functions in vivo.

The Group Migration of Dictyostelium Cells Is Regulated by Extracellular Chemoattractant Degradation

“…In leukocyte migration and inflammation, a role for various proteases as well as internalization of bound receptor by decoy receptors has been suggested to remove attractant molecules and regulate chemoattractant gradients (Borroni et al, 2008;Friedl and Weigelin, 2008;Leung et al, 2008;Scola et al, 2008). Interestingly, the pathogenic bacteria Pseudomonas aeruginosa seems to use degradation of proinflammatory factors to prevent host defenses from fighting the infection (Leidal et al, 2003).…”

“…In this context, cells internalize the bound receptor and as part of the receptor recycling pathway the ligand is released for degradation (Minina et al, 2007;Boldajipour et al, 2008;Borroni et al, 2008;Scola et al, 2008). Alternatively, extracellular enzymes can specifically degrade the extracellular signaling molecules, allowing the sensing machinery to go back to basal levels and retain high sensitivity (Leidal et al, 2003;Bader et al, 2007;Van Lint and Libert, 2007;Leung et al, 2008).…”

“…In this context, cells internalize the bound receptor and as part of the receptor recycling pathway the ligand is released for degradation (Minina et al, 2007;Boldajipour et al, 2008;Borroni et al, 2008;Scola et al, 2008). Alternatively, extracellular enzymes can specifically degrade the extracellular signaling molecules, allowing the sensing machinery to go back to basal levels and retain high sensitivity (Leidal et al, 2003;Bader et al, 2007;Van Lint and Libert, 2007;Leung et al, 2008).Dictyostelium is an excellent model system to study chemotaxis. These social amoebae occur naturally in the soil, and they exist in two independent life stages: a growth stage and a developmental stage (Chisholm and Firtel, 2004;Manahan et al, 2004;Mahadeo and Parent, 2006;Urushihara, 2008).…”

Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects

“…Thrombin binding to TM also enhances the substrate specificity of the latter toward thrombin-activatable fibrinolysis inhibitor (TAFI), a plasminogen-bound zymogen, to yield TAFIa (3,112). TAFIa-also known as procarboxypeptidase B2 (CPB2), carboxypeptidase U (CPU), and plasma carboxypeptidase (pCPB)-exhibits carboxypeptidase-like activity toward COOH-terminal lysine residues from partially degraded fibrin (82,193), thereby serving as a negative regulator of fibrinolysis. This enhances the stabilization of fibrin clots ensuring greater injury localization during vascular inflammatory events.…”

Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

“…First, C5a can induce the expression of tissue factor and plasminogen activator inhibitor-1, leading to amplification of coagulation and inhibition of fibrinolysis (43,44). The relation between C5a and coagulation pathways is reciprocal: thrombin directly cleaves C5 and generates active C5a, and thrombin-activatable carboxypeptidase B inhibits C5a (43,45). The procoagulant activity of C5a may represent an additional and/or additive factor in the vascular occlusion process in bacterial meningitis (24,46,47).…”