J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1401/06 $2.00
Volume 186, Number 8, October 20, 1997 1401-1406

BRIEF DEFINITIVE REPORT:
Suppression of Leukotriene B₄ Biosynthesis by Endogenous Adenosine in Ligand-activated Human Neutrophils

By Eric Krump,^* Serge Picard,^* Joseph Mancini, and Pierre Borgeat^*

From the ^* Centre de Recherche en Rhumatologie et Immunologie, Centre de recherche du CHUL et Université Laval, Québec, Canada; and  Merck Frosst Center for Therapeutic Research, Pointe-Claire, Québec, Canada

Adenosine (Ado) has been shown to suppress several functional responses of human polymorphonuclear leukocytes (PMNs). The current study investigated whether endogenous Ado regulates the biosynthesis of leukotriene (LT)B₄ in ligand-stimulated PMNs. Measurements of Ado in PMN resuspended in Hanks' buffered salt solution (HBSS) or plasma showed a cell concentration- and time-dependent accumulation of the nucleoside. The removal of endogenous Ado with either Ado deaminase or the blockade of its action by the Ado A_2a receptor antagonist, 8-(3-chlorostyryl) caffeine, markedly increased LTB₄ biosynthesis upon ligand stimulation in HBSS. Similarly, LTB₄ synthesis by ligand-stimulated PMNs in plasma (containing recombinant LTA₄ hydrolase to allow the conversion of protein-bound LTA₄) was strongly enhanced by addition of Ado deaminase. Addition of red blood cells to suspensions of PMNs in plasma mimicked the effect of adding Ado deaminase and LTA₄ hydrolase in enhancing LTB₄ biosynthesis upon ligand stimulation. This effect of red blood cells on LTB₄ biosynthesis was blocked by dipyridamole, an inhibitor of Ado transport, or captopril, an inhibitor of LTA₄ hydrolase. These results demonstrate that endogenous Ado efficiently downregulates ligand-stimulated LTB₄ biosynthesis in PMN suspensions, pointing out a potentially important regulatory function of Ado in inflammatory exudates. These results also unveil a dual role for red blood cells in upregulating LTB₄ biosynthesis, namely, the removal of endogenous Ado and the conversion of LTA₄ released by activated PMNs.

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