Intracellular function of interleukin-1 receptor antagonist in ischemic cardiomyocytes

PLoS One. 2013;8(1):e53265. doi: 10.1371/journal.pone.0053265. Epub 2013 Jan 8.

Abstract

Background: Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis.

Methodology/principal findings: Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra-/-) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized.

Conclusions/significance: These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Caspases / immunology
  • Cell Hypoxia
  • Cell Line
  • Gene Deletion
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / analysis
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / enzymology
  • Myocardial Ischemia / genetics
  • Myocardial Ischemia / immunology*
  • Myocardial Ischemia / pathology*
  • Myocardium / immunology
  • Myocardium / pathology*
  • Myocytes, Cardiac / immunology*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • RNA Interference
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Interleukin-1
  • Caspases