Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes

J Biol Chem. 2005 Feb 11;280(6):4553-67. doi: 10.1074/jbc.M411787200. Epub 2004 Dec 1.

Abstract

In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure.

Publication types

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

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Blotting, Northern
  • Blotting, Western
  • Cell Line
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chromones / pharmacology
  • Cytokines / metabolism*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • GATA4 Transcription Factor
  • Gene Expression Regulation
  • Genes, Reporter
  • Hypertrophy
  • Inflammation
  • Interleukin-18 / metabolism
  • Interleukin-18 / physiology*
  • Interleukin-18 Receptor alpha Subunit
  • Mice
  • Morpholines / pharmacology
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-18
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • GATA4 Transcription Factor
  • Il18r1 protein, mouse
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Morpholines
  • Proto-Oncogene Proteins
  • Receptors, Interleukin
  • Receptors, Interleukin-18
  • Transcription Factors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Atrial Natriuretic Factor
  • DNA
  • Phosphatidylinositol 3-Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Wortmannin