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

Abstract

Cytokines such as tumor necrosis factor alpha (TNF-alpha) 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-alpha production. The authors tested the hypothesis that stimulation of cardiac beta-adrenergic receptors would inhibit cytokine gene transcription induced by reactive oxygen. 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-alpha, interleukin-6, and cyclic AMP were measured in the coronary effluent. In control hearts, of the screened RNA, only mRNA encoding interleukin-1beta, -4, and -6 was detected. Stimulation with hypoxanthine-xanthine oxidase (HX-XO) induced detectable mRNA for TNF-alpha and interleukin-5 and increased mRNA band density for interleukin-1beta, -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-alpha was not detected in the coronary effluent. After HX-XO administration, TNF-alpha was reliably detected at 60 min and interleukin-6 at 90 min. Simultaneous infusion of isoproterenol inhibited TNF-alpha and interleukin-6 release. Inclusion of propranolol in the perfusion buffer blocked the isoproterenol-induced inhibition of HX-XO-stimulated TNF-alpha release and release of cyclic AMP into the coronary effluent. In addition, elevating myocardial cyclic AMP with forskolin also blocked release of TNF-alpha stimulated by HX-XO. Finally, delaying infusion of isoproterenol until 30 min after HX-XO administration still suppressed release of TNF-alpha. Reactive oxygen species activate cytokine gene transcription in the myocardium. The sympathetic nervous system, acting through beta-receptors to elevate myocardial cyclic AMP, regulates cardiac cytokine production by inhibition of transcription.