Effect of Theophylline and Adenosine on Eosinophil Function

Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced Superoxide anion (O2−) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10−3 M) inhibited O2− release by 27.6 ± 9.4% (mean ± SEM, p < 0.05), whereas at clinically relevant concentrations (10−6 and 10−5 M), it significantly potentiated this by 26.8 ± 9.9% (p < 0.05) and 36.9 ± 6.3% (p < 0.01), respectively. 8-phenyltheophylline (10−7 to 10−3 M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2− release by 72.4 ± 15.2% (p < 0.01), whereas addition of adenosine (3 × 10−8 to 10−6 M) reversed the potentiation induced by theophylline (10−5 M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2− release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.