Inactivation of C3a and C5a Octapeptides by Carboxypeptidase R and Carboxypeptidase N

Campbell, William; Lazoura, Eliada; Okada, Noriko; Okada, Hidechika

doi:10.1111/j.1348-0421.2002.tb02669.x

Cited by 200 publications

(174 citation statements)

References 18 publications

(16 reference statements)

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“…To test this, we studied the kinetics of TAFIa hydrolysis of BK and peptides based on the thrombincleaved OPN SVVYGLR motif and the C-terminal residues of C3a, C5a and compared these to peptides based on exposed C-terminal arginine or lysine sites on plasmin-degraded fibrin clots (27 It is interesting that plasma CPN, generally thought to be the physiological inactivator of the kinins and anaphylatoxins, hydrolyzed the fibrin peptides quite efficiently, suggesting a possible role of CPN in the maintenance of fibrin clot stability. CPN is more efficient in hydrolyzing C3a than C5a, while TAFIa shows the opposite preference, consistent with previous findings (13). On the other hand, in addition to C5a, TAFIa is also much more efficient than CPN in cleaving BK and OPN 160 -168 .…”

Section: Fig 1 Effect Of Tafia Treatment On Thrombin-cleaved Gst-opsupporting

confidence: 81%

“…DISCUSSION A major premise of this study is that TAFIa has broad substrate specificity, and by cleaving C-terminal arginine or lysine from a number of biologically active peptides, it functions as an anti-inflammatory molecule. Initial studies by Campbell and co-workers (4,12,13) showed that TAFIa could have a role as a regulator of inflammation by inactivation of kinins and anaphylatoxins. To test this, we studied the kinetics of TAFIa hydrolysis of BK and peptides based on the thrombincleaved OPN SVVYGLR motif and the C-terminal residues of C3a, C5a and compared these to peptides based on exposed C-terminal arginine or lysine sites on plasmin-degraded fibrin clots (27 It is interesting that plasma CPN, generally thought to be the physiological inactivator of the kinins and anaphylatoxins, hydrolyzed the fibrin peptides quite efficiently, suggesting a possible role of CPN in the maintenance of fibrin clot stability.…”

Section: Fig 1 Effect Of Tafia Treatment On Thrombin-cleaved Gst-opmentioning

confidence: 99%

“…Removal of the lysines reduces t-PA and plasminogen binding thereby reducing t-PA enhanced activation of plasmin (2, 3, 5-7). Recent studies also imply the possible role of TAFIa inactivation of kinins and anaphylatoxins (4,12,13). To show that kinins such as BK, anaphylatoxins such as complement C3a and C5a, and the thrombin-cleaved cytokine, OPN, are potential substrates of TAFIa, we determined their MichaelisMenten constants for hydrolysis by TAFIa.…”

Section: Bradykinin C5a and Thrombin-cleaved Osteopontin Werementioning

confidence: 99%

“…This anti-inflammatory role of aPC may contribute to its clinical efficacy in the treatment of severe sepsis (11). It has been proposed that TAFIa could also play a role in regulating inflammation by inactivation of kinins and anaphylatoxins through its arginine/ lysine specific carboxypeptidase activity (12,13). However, the efficiency of TAFIa in inactivating these biologically active mediators in comparison with carboxypeptidase N, the constitutively active plasma anaphylatoxin inhibitor, has not been defined.…”

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confidence: 99%

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Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Myles

Nishimura

Yun

et al. 2003

Journal of Biological Chemistry

206

202

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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 Arg 168 by TAFIa from the exposed SV-VYGLR ␣ 4 ␤ 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.

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Section: Fig 1 Effect Of Tafia Treatment On Thrombin-cleaved Gst-opsupporting

confidence: 81%

Section: Fig 1 Effect Of Tafia Treatment On Thrombin-cleaved Gst-opmentioning

confidence: 99%

Section: Bradykinin C5a and Thrombin-cleaved Osteopontin Werementioning

confidence: 99%

mentioning

confidence: 99%

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Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Myles

Nishimura

Yun

et al. 2003

Journal of Biological Chemistry

206

202

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“…CPB inactivates bradykinin, C3a and C5a. 18,19 We have demonstrated that CPB is much more efficient than CPN, the constitutively active plasma anaphylatoxin inhibitor, in cleaving these inflammatory peptides. CPB abrogated C5a-induced neutrophil activation in vitro, and, using an engineered anticoagulant thrombin, E229K, which activates plasma proCPB in mice, we showed that E229K thrombin blocked bradykinin-induced hypotension in wild-type (WT), but not in proCPB-deficient (proCPB Ϫ/Ϫ ) mice in vivo.…”

Section: Introductionmentioning

confidence: 99%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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Plasma procarboxypeptidase B (proCPB)is activated by the endothelial thrombinprothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPBdeficient mice (proCPB ؊/؊ ). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB ؊/؊ mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB ؊/؊ mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. IntroductionThe complement system is part of the innate immune system and plays a major role in the host defense against pyrogenic bacterial infection. 1,2 It is also involved in a wide variety of acute and chronic inflammatory disorders, including sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and glomerulonephritis. The complement system consists of multiple proteins in plasma and on cell surfaces and can be activated by 3 distinct pathways, all converging on the cleavage of C3 into C3a and C3b. C3b in turn becomes an essential component of the C5 convertase enzyme complex, leading to cleavage of C5 into C5a and C5b. Both C3a and C5a are strong chemoattractants. 1,2 They cause oxidative burst and enhance phagocytosis and granule enzyme release in neutrophils. They are vasodilators at sites of inflammation. C3a and C5a exert their effects through binding to cellular C3a receptors (C3aR) and C5a receptors (C5aR), respectively. C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. 2-4 Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.Thrombin-activatable procarboxypeptidase B (proCPB), also known as procarboxypeptidase U, procarboxypeptidase R, and thrombin-activatable fibrinolysis inhib...

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Complement System

Ward

Kemper

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Inactivation of C3a and C5a Octapeptides by Carboxypeptidase R and Carboxypeptidase N

Cited by 200 publications

References 18 publications

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Complement System

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