title: Intracellular function of interleukin-1 receptor antagonist in ischemic cardiomyocytes.
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.
  
  
  RESULTS
  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
  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.
authors: Department of Life Sciences, University of Trieste, Italy.
authors: Elena
authors: E
authors: Vecile
authors: Aldo
authors: A
authors: Dobrina
authors: Fadi N
authors: FN
authors: Salloum
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: Antonella
authors: A
authors: Falcione
authors: Edoardo
authors: E
authors: Gustini
authors: Samuele
authors: S
authors: Secchiero
authors: Sergio
authors: S
authors: Crovella
authors: Gianfranco
authors: G
authors: Sinagra
authors: Nicoletta
authors: N
authors: Finato
authors: Martin J
authors: MJ
authors: Nicklin
authors: Antonio
authors: A
authors: Abbate
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000276:immunology; D015687:Cell Hypoxia; D002460:Cell Line; D017353:Gene Deletion; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D017202:Myocardial Ischemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D020169:Caspases