beta -Adrenergic stimulation induces interleukin-18 expression via beta 2-AR, PI3K, Akt, IKK, and NF- Kappa B

We investigated whether beta -adrenergic receptor ( beta -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)- Kappa B. Our results indicate that isoproterenol (ISO) activates NF- Kappa B DNA binding activity, and induces myocardial and systemic elaboration of IL-18 via beta 2-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 beta 2-AR agonism. Signaling required Gi, PI3K, Akt, IKK, and NF- Kappa B. In conclusion, our results indicate for the first time that isoproterenol induces myocardial and systemic elaboration of IL-18 via a beta 2-AR and NF- Kappa B-dependent mechanism. Similar events may occur in heart failure, a disease state characterized by sustained beta -AR activation.