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Transcellular biosynthesis of sulfidopeptide leukotrienes during
receptor-mediated stimulation of human neutrophil/platelet mixtures
J Maclouf, RC Murphy and PM Henson
INSERM Unit 150, Hopital Lariboisiere, Paris, France.
The ability of different cell types to cooperate in the metabolism of
reactive intermediates of arachidonic acid such as leukotriene A4 (LTA4) is
currently receiving considerable attention. Of critical importance is the
demonstration that transfer of LTA4 could occur under conditions when
relatively low amounts of LTA4 are produced such as would be expected for
in vitro receptor-mediated stimulation. Stimulation of human neutrophils
with a combination of chemotactic factor
(formyl-methionyl-leucyl-phenylalanine, FMLP) and phagocytosable particles
(opsonized zymosan) resulted in little production of LTC4 alone, but
measurable quantities appeared when platelets were coincubated. When these
agonists were added to platelets alone in the absence of neutrophils, no
LTC4 was produced. In the presence of stimulated neutrophils, the final
synthesis of LTC4 was shown to occur within the platelets (from
neutrophil-derived LTA4) by experiments using platelets that had been
prelabeled with 35S-cysteine to label intracellular platelet glutathione.
Other 35S-labeled sulfidopeptide leukotriene metabolites were also produced
in this coincubation of neutrophils and platelets. The observed synergy
between FMLP and opsonized zymosan in the production of LTC4 when
neutrophils and platelets were coincubated may involve priming the
neutrophil for LTA4 production. Activation of platelets or endothelial
cells with thrombin did not alter the capacity of either cell to convert
exogenously added LTA4 into LTC4. This would support the suggestion that
even when platelets are activated they retain their capacity to metabolize
LTA4 into LTC4. Finally, previous exposure of the platelets to LTA4 did not
affect subsequent metabolism of arachidonic acid by the cyclooxygenase
pathway to thromboxane A2 (TXA2) except at very high concentration of LTA4.
These results suggest that cell-cell interactions may be critical
determinants of the profile of eicosanoids produced in physiologic and
pathophysiologic circumstances. In particular, we believe that both
endothelial cells and platelets can, together with neutrophils, contribute
relatively large amounts of sulfidopeptide leukotrienes to inflammatory and
thrombotic events. These cell-cell interactions are aspirin-insensitive;
therefore, aspirin-treated platelets are capable of synthesizing the
vasoconstrictor LTC4 from neutrophil LTA4 at a time when they can no longer
produce thromboxane.
Volume 76,
Issue 9,
pp. 1838-1844,
11/01/1990
Copyright © 1990 by The American Society of Hematology
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