Effect of leukocyte proteinases on tissue factor pathway inhibitor.
The effect of human neutrophil elastase and cathepsin G on recombinant tissue factor pathway inhibitor (TFPI) was investigated. A weak inhibition by TFPI of both elastase (Ki = 0.4 microM) and cathepsin G (Ki = 0.1 microM) was observed. Neutrophil elastase rapidly cleaved TFPI at the Thr87-Thr88 bond situated at the link between Kunitz domains I and II. Cleavage of TFPI by cathepsin G was also observed, but the reaction was much slower and resulted in a number of fragments. Proteolytic cleavage by both elastase and cathepsin G resulted in destruction of inhibitor function with respect to TFPI's inhibition of factor Xa. Cleavage by neutrophil elastase was capable of restoring factor Xa amidolytic activity after its initial inhibition by TFPI. Inhibition of cathepsin G by TFPI was strongly augmented by stoichiometric amounts of factor Xa. However, the augmentation was temporary, presumably due to concomitant cleavage of TFPI by cathepsin G. These observations may have implications for the putative effect of neutrophil leukocyte stimulation on the regulation of the tissue factor-mediated coagulation pathway. Conversely, formation of a factor Xa/TFPI complex may reduce or modulate the proteolytic potential of stimulated leukocytes by temporary inhibition of cathepsin G.
Petersen
L C
LC
Novo Nordisk Research Institute, Denmark.
Bjørn
S E
SE
Nordfang
O
O
D000595:Amino Acid Sequence; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000097:blood*; D065427:Factor Xa Inhibitors; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000097:blood*; D011480:Protease Inhibitors / Q000097:blood*; D011994:Recombinant Proteins / Q000097:blood; D012697:Serine Endopeptidases
D065427:Factor Xa Inhibitors; D008074:Lipoproteins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase