ADENOSINE INHIBITS NEUTROPHIL DEGRANULATION IN ACTIVATED HUMAN WHOLE-BLOOD - INVOLVEMENT OF ADENOSINE A2 AND A3 RECEPTORS

Adenosine, acting via A2 receptors, is a potent inhibitor of neutrophi l oxidative burst, but its effects and mechanisms of action on neutrop hil degranulation have been less well characterized, We, therefore, in vestigated the effects of adenosine and its receptor-specific analogue s on neutrophil degranulation in stimulated human whole blood, Adenosi ne dose-dependently inhibited the LPS-and TNF-alpha-induced release of the azurophilic granule proteins bactericidal/permeability-increasing protein, elastase, and defensins to approximately the same extent, wi th a maximum inhibition of 70 to 80% and an IC50 ranging from 14 to 24 mu M. The inhibitory effects of adenosine were partially blocked by t he A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, the A1/A2 antagonist 8(p-sulfophenyl)theophyline, and the A1/A3 antagonist xanth ine amine congener, but not by the A1 antagonist 1,3-dipropyl-8-cyclop entylxanthine. The highly selective A3 agonist N-6-(3-iodobenzyl)-aden osine-5'-N-methyluronamide and the nonselective agonist 2-chloroadenos ine reduced degranulation more potently than the A1 agonist N-6-cyclop entyladenosine. The inhibitory effects of N-6-(3-iodobenzyl)-adenosine -5'-N-methyluronamide and 2-chloroadenosine were strongly reversed by xanthine amine congener, but were not affected by 8(p-sulfophenyl)theo phyline. In addition, the adenosine kinase inhibitor GP515 attenuated degranulation via an adenosine-mediated mechanism, These data indicate that adenosine acts via A2 as well as A3 receptors to inhibit neutrop hil degranulation and add to the anti-inflammatory potential of adenos ine and adenosine-regulating agents in neutrophil-mediated tissue inju ry.