Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation.
The latent plasma carboxypeptidase thrombin-activable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. In this study, we examined the effect of activated TAFI (TAFIa) in modulating the proinflammatory functions of bradykinin, complement C5a, and thrombin-cleaved osteopontin. Hydrolysis of bradykinin and C5a and thrombin-cleaved osteopontin peptides by TAFIa was as efficient as that of plasmin-cleaved fibrin peptides, indicating that these are also good substrates for TAFIa. Plasma carboxypeptidase N, generally regarded as the physiological regulator of kinins, was much less efficient than TAFIa. TAFIa abrogated C5a-induced neutrophil activation in vitro. Jurkat cell adhesion to osteopontin was markedly enhanced by thrombin cleavage of osteopontin. This was abolished by TAFIa treatment due to the removal of the C-terminal Arg168 by TAFIa from the exposed SVVYGLR alpha 4 beta 1 integrin-binding site in thrombin-cleaved osteopontin. Thus, thrombin cleavage of osteopontin followed by TAFIa treatment may sequentially up- and down-modulate the pro-inflammatory properties of osteopontin. An engineered anticoagulant thrombin, E229K, was able to activate endogenous plasma TAFI in mice, and E229K thrombin infusion effectively blocked bradykinin-induced hypotension in wild-type, but not in TAFI-deficient, mice in vivo. Our data suggest that TAFIa may have a broad anti-inflammatory role, and its function is not restricted to fibrinolysis.
Myles
Timothy
T
Division of Hematology, Department of Medicine, Stanford University School of Medicine, California 94305, USA. tmyles@stanford.edu
Nishimura
Toshihiko
T
Yun
Thomas H
TH
Nagashima
Mariko
M
Morser
John
J
Patterson
Andrew J
AJ
Pearl
Ronald G
RG
Leung
Lawrence L K
LL
D000818:Animals; D001773:Blood Cells; D001920:Bradykinin / Q000378:metabolism; D025901:Carboxypeptidase B2 / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D015926:Complement C3a / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D007022:Hypotension; D007249:Inflammation / Q000209:etiology*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000378:metabolism; D013917:Thrombin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D015926:Complement C3a; D015936:Complement C5a; D025901:Carboxypeptidase B2; D013917:Thrombin; D001920:Bradykinin