Summary
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
(Kx
= 0.4 μM) and cathepsin G (Kx
= 0.1 μM) 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 amidoly-tic 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.
