Isoproterenol inhibits transcription of cardiac cytokine genes induced by reactive oxygen intermediates

Background: Cytokines such as tumor necrosis factor α (TNF-α) are produced by the myocardium in heart disease and might be stimulated by reactive oxygen. In some cell types, cyclic adenosine monophosphate (AMP) inhibits TNF-α production. The authors tested the hypothesis that stimulation of cardiac β-adrenergic receptors would inhibit cytokine gene transcription induced by reactive oxygen. Methods: Rat hearts were perfused with buffer containing hypoxanthine. Reactive oxygen intermediates were generated by infusion of xanthine oxidase. Myocardial mRNA encoding 11 cytokines was determined. TNF-α, interleukin-6, and cyclic AMP were measured in the coronary effluent. Results: In control hearts, of the screened RNA, only mRNA encoding interleukin-1β, -4, and -6 was detected. Stimulation with hypoxanthine-xanthine oxidase (HX-XO) induced detectable mRNA for TNF-α and interleukin-5 and increased mRNA band density for interleukin-1β, -4, and -6. Simultaneous infusion of isoproterenol inhibited HX-XO-stimulated cytokine gene expression and caused release of cyclic AMP into the coronary effluent. In control hearts, TNF-α was not detected in the coronary effluent. After HX-XO administration, TNF-α was reliably detected at 60 min and interleukin-6 at 90 min. Simultaneous infusion of isoproterenol inhibited TNF-α and interleukin-6 release. Inclusion of propranolol in the perfusion buffer blocked the isoproterenol-induced inhibition of HX-XO-stimulated TNF-α release and release of cyclic AMP into the coronary effluent. In addition, elevating myocardial cyclic AMP with forskolin also blocked release of TNF-α stimulated by HX-XO. Finally, delaying infusion of isoproterenol until 30 min after HX-XO administration still suppressed release of TNF-α. Conclusions: Reactive oxygen species activate cytokine gene transcription in the myocardium. The sympathetic nervous system, acting through β-receptors to elevate myocardial cyclic AMP, regulates cardiac cytokine production by inhibition of transcription.