Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.
Unstimulated neutrophils inhibited activation and recruitment of thrombin- or collagen-stimulated platelets in an agonist-specific manner. This occurred under conditions of close physical cell-cell contact, although biochemical adhesion between the cells as mediated by P-selectin was not required. Moreover, in the presence of monoclonal P-selectin antibodies that blocked biochemical platelet-neutrophil adhesion, thrombin-stimulated platelets were more efficiently downregulated by neutrophils. This suggested a prothrombotic role for P-selectin under these circumstances. The neutrophil downregulatory effect on thrombin-stimulated platelets was amplified by lipoxygenase inhibition with 5,8,11,14-eicosatetraynoic acid. In contrast, the neutrophil inhibitory effect on platelets was markedly reduced by platelet-derived 12S-hydroxy-5,8-cis, 10-trans, 14-cis-eicosatetraenoic acid (12S-HETE), as well as by the platelet-neutrophil transcellular product, 12S,20-dihydroxy-5,8,10,14-eicosatetraenoic acid (12S,20-DiHETE), but not by another comparable metabolite, 5S,12S-dihydroxy-6-trans, 8-cis, 10-trans, 14-cis-eicosatetraenoic acid (5S,12S-DiHETE), or the neutrophil-derived hydroxy acid leukotriene B4. The neutrophil downregulatory effect on thrombin-induced platelet reactivity was enhanced by aspirin treatment. This may represent a novel action of aspirin as an inhibitor of platelet function. These results provide in vitro biochemical and functional evidence for the thromboregulatory role of neutrophils and emphasize the multicellular aspect of hemostasis and thrombosis.
Valles
J
J
Department of Medicine, Department of Veterans Affairs Medical Center, New York, New York 10010.
Santos
M T
MT
Marcus
A J
AJ
Safier
L B
LB
Broekman
M J
MJ
Islam
N
N
Ullman
H L
HL
Aznar
J
J
D000244:Adenosine Diphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000502:physiology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D015777:Eicosanoids / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019007:P-Selectin; D015539:Platelet Activation; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D012697:Serine Endopeptidases / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D015777:Eicosanoids; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D009569:Nitric Oxide; D012701:Serotonin; D000244:Adenosine Diphosphate; D003094:Collagen; D008084:Lipoxygenase; D012697:Serine Endopeptidases; D013917:Thrombin