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Specific inhibition of thrombin-induced cell activation by the neutrophil
proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct
cleavage sites within the aminoterminal domain of the thrombin receptor
P Renesto, M Si-Tahar, M Moniatte, V Balloy, A Van Dorsselaer, D Pidard and M Chignard
Unite de Pharmacologie Cellulaire, Institut Pasteur, Paris, France.
The aim of this study was to investigate the inhibitory effects of human
leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR3) on
the activation of endothelial cells (ECs) and platelets by thrombin and to
elucidate the underlying mechanisms. Although preincubation of ECs with HLE
or Cat G prevented cytosolic calcium mobilization and prostacyclin
synthesis induced by thrombin, these cell responses were not affected when
triggered by TRAP42-55, a synthetic peptide corresponding to the sequence
of the tethered ligand (Ser42- Phe55) unmasked by thrombin on cleavage of
its receptor. Using IIaR-A, a monoclonal antibody directed against the
sequence encompassing this cleavage site, flow cytometry analysis showed
that the surface expression of this epitope was abolished after incubation
of ECs with HLE or Cat G. Further experiments conducted with platelets
indicated that not only HLE and Cat G but also PR3 inhibited cell
activation induced by thrombin, although they were again ineffective when
TRAP42- 55 was the agonist. Similar to that for ECs, the epitope for IIaR-A
disappeared on treatment of platelets with either proteinase. These results
suggested that the neutrophil enzymes proteolyzed the thrombin receptor
downstream of the thrombin cleavage site (Arg41-Ser42) but left intact the
TRAP42-55 binding site (Gln83-Ser93) within the extracellular aminoterminal
domain. The capacity of these proteinases to cleave five overlapping
synthetic peptides mapping the portion of the receptor from Asn35 to Pro85
was then investigated. Mass spectrometry studies showed several distinct
cleavage sites, i.e., two for HLE (Val(72)-Ser73 and Ile74-Asn75), three
for Cat G (Arg41-Ser42, Phe55-Trp56 and Tyr69-Arg70), and one for PR3
(Val(72)-Ser73). We conclude that this singular susceptibility of the
thrombin receptor to proteolysis accounts for the ability of neutrophil
proteinases to inhibit cell responses to thrombin.
Volume 89,
Issue 6,
pp. 1944-1953,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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