Adenosine A2a 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-ethylcarboxamidoadenosine (NECA) decreased apoptosis after 16 h, with half-maximal responses for NECA and 2-chloroadenosine of 7.1 +/- 7.7 and 59.0 +/- 32.0 nM, respectively. Adenosine receptor agonists exhibited a rank order of potency for decreasing apoptosis of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) > NECA > or = 2-chloro-N6-cyclopentyladenosine >> 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide, which is consistent with the affinity order profile established for human A2a receptors. The reduction in apoptosis in cultured neutrophils at 16 h by CGS 21680 was due to a delay in apoptosis. The addition of CGS 21680 (100 nM) increased the half-life for the appearance of apoptosis from 10.9 +/- 3.1 to 21.0 +/- 1.0 h. Addition of the non-xanthine phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazalidinone (Ro-20-1724; 1 microM) enhanced the effects of CGS 21680 at all agonist concentrations. PGE1 (10 microM), PGE2 (0.1-10 microM), and dibutyryl cAMP (5-500 microM) all decreased apoptosis in cultured neutrophils. The enhancement of the effect of adenosine by a phosphodiesterase inhibitor and the similar actions of PGE2, PGE1, and dibutyryl cAMP suggest that this decrease in apoptosis may be mediated by a cAMP-dependent pathway.
Walker
B A
BA
University of British Columbia Pulmonary Research Laboratory, Vancouver, Canada.
Rocchini
C
C
Boone
R H
RH
Ip
S
S
Jacobson
M A
MA
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000097:blood*; D013997:Time Factors
D010627:Phenethylamines; D010726:Phosphodiesterase Inhibitors; D011453:Prostaglandins; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D003994:Bucladesine; D000241:Adenosine