β-Adrenergic stimulation induces interleukin-18 expression via β2-AR, PI3K, Akt, IKK, and NF-κB

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 G_i, 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.