Suppressive effects of adenosine on the 5-lipoxygenase pathway in human polymorphonuclear leukocytes

Leukotrienes are potent mediators of inflammation and host defense. They ar e also involved in inflammatory and allergic diseases. While numerous studi es have investigated the stimulatory mechanisms of leukotriene biosynthesis in phagocytes by inflammatory agents (chemoattractants, cytokines, etc.), the mechanisms responsible for the physiological downregulation of leukotri ene biosynthesis have been the subject of very few investigations so far. I t has, however, been reported that E-type prostaglandins are potent inhibit ors of leukotriene biosynthesis in chemoattractant-stimulated neutrophils a nd Lye have recently shown with in vitro studies that endogenous adenosine is a potent inhibitor of leukotriene biosynthesis by neutrophils. The prese nt review summarizes our studies demonstrating that adenosine downregulates leukotriene biosynthesis via an interaction with the adenosine A(2)a, rece ptor on neutrophils; studies aimed at defining the mechanisms of action of adenosine in this process have demonstrated that adenosine inhibits the tra nslocation of the cytosolic enzyme 5-lipoxygenase to nuclear structures, a process required for leukotriene biosynthesis in neutrophils. Our studies a lso demonstrated that exposure of human neutrophils to the adenosine A(2a) receptor agonist CGS-21680 result in a profound inhibition of the release o f arachidonic acid upon cell stimulation. While the previously reported inh ibitory effect of adenosine on calcium influx elicited in ligand-activated neutrophils does not appear to be involved in the inhibitory effects of ade nosine on leukotriene biosynthesis, strong evidence supports the implicatio n of elevation of intracellular cyclic AMP concentration both in the inhibi tion of 5-lipoxygenase translocation and arachidonic acid release. Drug Dev Res. 52:397-405, 2001. (C) 2001 Wiley-Liss, Inc.