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

J Mol Cell Cardiol. 2012 Jan;52(1):206-18. doi: 10.1016/j.yjmcc.2011.09.022. Epub 2011 Oct 8.

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 β(2)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / adverse effects
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Animals
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cardiomegaly / chemically induced
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Expression Regulation / drug effects*
  • Gene Knockout Techniques
  • 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
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects

Substances

  • Adrenergic beta-2 Receptor Agonists
  • CCAAT-Enhancer-Binding Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • Receptors, Adrenergic, beta-2
  • interleukin-18 binding protein
  • Isoproterenol