Abstract 8393: IL-18 Binding Protein (IL-18BP) Inhibits β-AR Induced Cardiomyocyte Hypertrophy in vitro and Myocardial Hypertrophy in vivo
Crosstalk between the sympathetic nervous system and proinflammatory cytokines such as interleukin-18 (IL-18) plays a key role in the pathophysiology of the hypertrophied failing heart. Importantly, IL-18 can directly promote cardiomyocyte hypertrophy. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18, and counters its biological effects. While β-AR stimulation induces IL-18, it is not known whether it also regulates IL-18BP. Here we demonstrate that the β-AR agonist isoproterenol (ISO) upregulates IL-18BP mRNA and protein expression in adult mouse cardiomyocytes in β2-AR/Gi-dependent manner. We cloned mouse Il18bp 5’cis-regulatory region, and identified several putative transcription factor-binding sites, including CREB, C/EBP, NF-kB, and Sp1. While forced expression of dnp65 or kdIKKβ, or pre-treatment with mithramycin (Sp1 inhibitor) had no significant effect, forced expression of dnCREB or C/EBPβ knockdown markedly attenuated ISO-induced Il18bp transcription. ISO induced Il18bp promoter-reporter activity, and the deletion or mutation of CREB and C/EBP motifs reduced the response. ISO induced CREB and C/EBPβ DNA-binding activity, reporter gene activation, and in vivo binding to Il18bp promoter. ISO induced CREB and C/EBPβ activation via PI3K/Akt and ERK1/2. Importantly, ISO-induced hypertrophy (increased cell surface area and protein and not DNA synthesis) was blunted in cardiomyocytes isolated from IL-18BP Tg mice, by the forced expression of IL-18BP, and IL-18 neutralizing Ab. Further, ISO treatment in vivo was associated with Akt and ERK1/2 phosphorylation, CREB and C/EBPβ activation, and IL-18BP expression. Notably, ISO-induced myocardial hypertrophy was markedly attenuated in IL-18BP Tg mice. These data provide the first evidence that ISO induces mouse IL-18BP expression in cardiomyocytes via β2-AR/Gi-mediated Akt and ERK1/2-dependent CREB and C/EBPβ activation. Moreover, IL-18BP inhibits ISO-induced cardiomyocyte hypertrophy both in vitro and in vivo, likely via prevention of the biologic effects of IL-18. Thus, catecholamine induced expression of IL-18BP may play a protective role in the hypertrophied failing heart, a disease state characterized by sustained β-AR activation and IL-18 signaling.
- © 2011 by American Heart Association, Inc.