β2 adrenergic activation induces the expression of IL-18 binding protein, a potent inhibitor of isoproterenol induced cardiomyocyte hypertrophy in vitro and myocardial hypertrophy in vivo

• Published in: Journal of molecular and cellular cardiology 2012-01, Vol.52 (1), p.206-218
• Main Authors: Murray, David R, Mummidi, Srinivas, Valente, Anthony J, Yoshida, Tadashi, Somanna, Naveen K, Delafontaine, Patrice, Dinarello, Charles A, Chandrasekar, Bysani
• Format: Article
• Language: English
• Subjects: Adrenergic beta-2 Receptor Agonists - adverse effects; Adrenergic beta-2 Receptor Agonists - pharmacology; Adrenergic stimulation; Animals; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiovascular; CCAAT-Enhancer-Binding Proteins - metabolism; Cloning; Cyclic AMP Response Element-Binding Protein - metabolism; Gene Expression Regulation - drug effects; Gene Knockout Techniques; Heart failure; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin-18 - genetics; Interleukin-18 - metabolism; Isoproterenol - adverse effects; Isoproterenol - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular mechanism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Signal transduction; Signal Transduction - drug effects; Transcription; Transcription, Genetic - drug effects
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2011.09.022

Abstract Both the sympathetic nervous system and the proinflammatory cytokine interleukin-18 (IL-18) play key roles in the pathophysiology of the hypertrophied failing heart. IL-18 binding protein (IL-18BP), a natural inhibitor of IL-18, counters its biological effects. β-AR stimulation induces IL-18 expression, but whether it also regulates IL-18BP is not known. Here we demonstrate that the β-AR agonist isoproterenol (ISO) increases steady state IL-18BP mRNA and protein levels in adult mouse cardiomyocytes in a β2 -AR-dependent manner. We cloned mouse Il18bp 5′ cis -regulatory region, and identified putative CREB and C/EBPβ transcription factor-binding sites. Forced expression of mutant CREB or C/EBPβ knockdown markedly attenuated ISO-induced Il18bp transcription and deletion or mutation of CREB and C/EBP motifs in the Il18bp promoter reduced ISO-induced promoter-reporter gene activity. ISO induced CREB and C/EBPβ activation in cardiomyocytes via PI3K/Akt and ERK1/2. Importantly, ISO-induced hypertrophy in vitro was dependent on IL-18 induction as it was blunted by IL-18 neutralizing antibodies and forced expression of IL-18BP. Moreover, ISO-induced hypertrophy was markedly attenuated in IL-18 null and IL-18BP transgenic mice. These data support the novel concept that β-AR activation, in addition to inducing cardiomyocyte hypertrophy via IL-18, concomitantly induces a countering effect by stimulating IL-18BP expression, and that ISO-induced cardiomyocyte hypertrophy may result from a net effect of IL-18 and IL-18BP induction.