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Theophylline induces neutrophil apoptosis through adenosine A 2A receptor antagonism
Author(s) -
Yasui Kozo,
Agematsu Kazunaga,
Shinozaki Koji,
Hokibara Sho,
Nagumo Haruo,
Nakazawa Takayuki,
Komiyama Atsushi
Publication year - 2000
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.67.4.529
Subject(s) - adenosine receptor , biology , adenosine receptor antagonist , adenosine , agonist , antagonism , theophylline , receptor , pharmacology , adenosine a3 receptor , cgs 21680 , apoptosis , adenosine a2a receptor , medicine , endocrinology , biochemistry
This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A 2A receptor antagonism. A selective adenosine A 2 receptor agonist (CGS‐21680, 1 μM) 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 μM) reversed the capacity of dibu‐tyryl cAMP but not CGS‐21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A 2 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 A 2A receptors. Theophylline demonstrated an additive effect to that of anti‐Fas antibody (CH11, 1 μg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF‐17837 (a selective A 2 receptor antagonist; 1 μM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A 2A antagonism. J. Leukoc. Biol. 67:529–535; 2000.