Proteinase 3. A neutrophil proteinase with activity on platelets.
Purified proteinase 3 (PR3) devoid of any elastase (HLE) and cathepsin G (Cat.G) contaminants, was prepared from azurophilic granules of human polymorphonuclear neutrophils by using a novel procedure. Although unable to induce platelet activation (up to 25 micrograms/ml) by itself, PR3 at a concentration as low as 2.5 micrograms/ml enhanced the platelet response to a concomitantly added threshold concentration of Cat.G, a recognized platelet agonist. In the presence of 10 micrograms/ml PR3, aggregation and degranulation of platelets induced by Cat.G were 43.2 +/- 5.9% and 27.1 +/- 1.9% as compared with 5.5 +/- 2.9% and 4.2 +/- 1.5% (n = 4) for Cat.G alone. This enhancing effect by PR3 was also observed with collagen and a cyclic endoperoxide analogue, and was inhibited by eglin C and elafin, two PR3 inhibitors. Associated with the removal of activity by a anti-PR3 mAb and the lack of effect of the secretory leukocyte proteinase inhibitor, these data demonstrated that the effect is specifically related to the enzymatic activity of PR3. It is hypothesized that this mechanism could play a role in the polymorphonuclear neutrophil-mediated platelet activation, an event already known to be dependent on Cat.G and HLE. This is supported by the fact that the association of PR3 and HLE, at concentrations ineffective by themselves, was able to potentiate Cat.G-induced platelet activation.
Renesto
P
P
Cell Pharmacology Unit, Associated Unit IP/INSERM 285, Pasteur Institute, Paris, France.
Halbwachs-Mecarelli
L
L
Nusbaum
P
P
Lesavre
P
P
Chignard
M
M
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D053146:Myeloblastin; D009504:Neutrophils / Q000201:enzymology*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D012697:Serine Endopeptidases / Q000097:blood* / Q000302:isolation & purification / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism
D012701:Serotonin; D003094:Collagen; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D053146:Myeloblastin