Thrombin-activatable Carboxypeptidase B Prevents Anti-Collagen Antibody Induced Arthritis

Song, Jaeyong; Nishimura, Toshihiko; Garcia, Michael; Myles, Timothy; Ho, Peggy; Du, Xiaoyan; Sharif, Shadi; Leung, Lawrence L.K.; Robinson, William A.

doi:10.1016/j.clim.2007.03.459

Cited by 2 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both OPN, and specifically thrombin-cleaved OPN, as well as C5a have been reported to play an important role in this process. ProCPB-deficient mice developed enhanced arthritis in this model, with significant swelling in the paws and histology confirmed significant inflammatory cell infiltration in the synovial tissues (Song et al, 2007). C5a plays a key role in this model since C5-deficient mice were protected from arthritis development.…”

Section: Procpb-deficient Mice Are Predisposed To Inflammatory Artmentioning

confidence: 84%

Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI)

Leung

Myles

Nishimura

et al. 2008

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Procpb-deficient Mice Are Predisposed To Inflammatory Artmentioning

confidence: 84%

Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI)

Leung

Myles

Nishimura

et al. 2008

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

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

Leung

Nishimura

Myles

2008

Advances in Experimental Medicine and Biology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Thrombin-activatable Carboxypeptidase B Prevents Anti-Collagen Antibody Induced Arthritis

Cited by 2 publications

References 0 publications

Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI)

Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI)

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

Contact Info

Product

Resources

About