ADENOSINE A(2A) RECEPTOR ACTIVATION DELAYS APOPTOSIS IN HUMAN NEUTROPHILS

Adenosine has both pro- and anti-inflammatory effects on neutrophils. Exposure of cultured neutrophils to 2-chloroadenosine or 5'-N-ethylcar boxamidoadenosine (NECA) decreased apoptosis after 16 h, with half-max imal responses for NECA and 2-chloroadenosine of 7.1 +/- 7.7 and 59.0 +/- 32.0 nM, respectively. Adenosine receptor agonists exhibited a ran k order of potency for decreasing apoptosis of thyl)phenethylamino-5'- N-ethylcarboxamidoadenosine (CCS 21680) > NECA greater than or equal t o 2-chloro-N-6-cyclopentyladenosine >> -N-6-(3-iodobenzyl)adenosine-5' -N-methyluronamide, which is consistent with the affinity order profil e established for human A(2a) receptors. The reduction in apoptosis in cultured neutrophils at 16 h by CCS 21680 was due to a delay in apopt osis, The addition of CGS 21680 (100 nM) increased the half-life for t he appearance of apoptosis from 10.9 +/- 3.1 to 21.0 +/- 1.0 h. Additi on of the non-xanthine phosphodiesterase inhibitor 4-(3-butoxy-4-metho xybenzyl)-2-imidazalidinone (Ro-20-1724; 1 mu M) enhanced the effects of CGS 21680 at all agonist concentrations, PGE(1) (10 mu M), PGE(2) ( 0.1-10 mu M), and dibutyryl cAMP (5-500 mu M) all decreased apoptosis in cultured neutrophils. The enhancement of the effect of adenosine by a phosphodiesterase inhibitor and the similar actions of PGE(1), PGE( 1), and dibutyryl cAMP suggest that this decrease in apoptosis may be mediated by a cAMP-dependent pathway.