Involvement of A(3) receptors in the potentiation by adenosine of the inhibitory effect of theophylline on human eosinophil degranulation: possible novel mechanism of the anti-inflammatory action of theophylline.
The current use of theophylline in asthma is based on both the bronchodilatory and the anti-inflammatory effects. The exact mechanism of these actions is still controversial and may include the inhibition of adenosine 3',5'-monophosphate phosphodiesterase enzyme (PDE) and antagonism of adenosine receptors. In this study, the mechanism of the anti-inflammatory action was investigated by studying the inhibition by theophylline of complement C5a (C5a)-induced degranulation of human eosinophils and its interaction with adenosine. Theophylline (10-1000 microM) inhibited C5a-induced release of eosinophil peroxidase (EPO) in a concentration-dependent manner with an IC(50) of 233.5 microM and a maximal inhibition of 90.3 +/- 3.0%. In contrast, the PDE4 inhibitor rolipram (up to 50 microM) had no effect. The adenosine A(3) receptor agonist N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) also inhibited release (IC(50) = 7.5 microM), but neither adenosine itself nor the selective A(1) and A(2) agonists and antagonists had any significant effect, even at 100 microM. The inhibition produced by clinically relevant concentration of theophylline (50 microM) was potentiated by ineffective concentrations of exogenous adenosine and additive to that produced by IB-MECA. The potent and selective A(3) antagonist MRS 1220, but not the A(1) or A(2) antagonists, significantly reversed the inhibitory effect of theophylline. These results suggest that therapeutic concentrations of theophylline inhibit human eosinophil partly by acting as an A(3) agonist. Together with the potentiation of theophylline action by adenosine, perhaps via the A(3) receptors, these novel actions may, at least in part, contribute to the mechanism of the anti-inflammatory action of this drug in vivo.
Ezeamuzie
C I
CI
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait. ezeamuzie@hsc.kuniv.edu.kw
D000241:Adenosine / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D004347:Drug Interactions; D004357:Drug Synergism; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D010544:Peroxidases / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D013806:Theophylline; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D000241:Adenosine