Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism.
This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.
Yasui
K
K
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. koyasui@gipac.shinshu-u.ac.jp
Agematsu
K
K
Shinozaki
K
K
Hokibara
S
S
Nagumo
H
H
Nakazawa
T
T
Komiyama
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002227:Carbazoles; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D010627:Phenethylamines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011758:Pyrroles / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D015398:Signal Transduction / Q000276:immunology; D013806:Theophylline / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D002227:Carbazoles; D007211:Indoles; D010627:Phenethylamines; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D011758:Pyrroles; D043705:Receptor, Adenosine A2A; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081198:KF 17837; C057416:KT 5720; D013806:Theophylline; D000241:Adenosine