We investigated whether β-adrenergic receptor (β-AR) stimulation induces the expression of interleukin (IL)-18, a proinflammatory cytokine, in myocardium and in cardiac-derived endothelial cells (CDEC) via activation of nuclear factor (NF)-κB. Our results indicate that isoproterenol (ISO) activates NF-κB DNA binding activity, and induces myocardial and systemic elaboration of IL-18 via β2-AR signaling. Furthermore, in CDEC, ISO increased basal and inducible promoter activities, increased IL-18 gene transcription and mRNA stability, and induced IL-18 expression via β2-AR agonism. Signaling required Gi, PI3K, Akt, IKK, and NF-κB. In conclusion, our results indicate for the first time that isoproterenol induces myocardial and systemic elaboration of IL-18 via a β2-AR and NF-κB-dependent mechanism. Similar events may occur in heart failure, a disease state characterized by sustained β-AR activation. © 2004 Elsevier Inc. All rights reserved.