Biphasic effect of ATP on neutrophil functions mediated by P-2U and adenosine A(2A) receptors

In agreement with previous findings, the oxidative burst induced by Met-Leu-Phe (tMLP) in polymorphonuclear neutrophils was enhanced by adenosine triphosphate (ATP) and uridine 5'-triphosphate (UTP), although these nucleotides were inactive as agonists per se. However, the enhancement by ATP was rapidly reversed to an inhibition by prolonged incubation. Adenosine diphosphate (ADP) was always inhibitory. Inhibition mediated by ATP coincided with its conversion into ADP, adenosine monphosphate (AMP), and adenosine. In addition, the inhibitory effects of ATP and ADP on the oxidative burst were virtually abolished by 9-chloro-2-(2-furanyl)-5,6-dihydro-[1,2,4]-triazolo[1,5] quinazolin-5-imine monomethanesulfonate (CGS 15943), a nonselective adenosine receptor antagonist, whereas the priming effect of ATP was antagonized by adenosine. Both ATP and UTP showed a similar potency in activating elastase release, intracellular inositol-(1,4,5)-triphosphate (IP3) formation and an increase in cytosolic calcium. Neither ATP nor UTP affected the initial rise in cytosolic calcium induced by fMLP, bur did enhance the secondary calcium increase. When added simultaneously with tMLP, ADP and adenosine abolished this second calcium peak without influencing the first. These results indicate that purine and pyrimidine nucleotides acting on P-2U-like receptors, which are coupled to the IP3 pathway, can increase calcium, release elastase, and enhance the oxidative burst induced by chemokines. Adenosine formed by hydrolysis from ATP and ADP, by contrast, reduces the oxidative burst and the influx of extracellular calcium induced by fMLP.