Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1β or IL-1 receptor type I

APMIS. 2010 Dec;118(12):1000-7. doi: 10.1111/j.1600-0463.2010.02684.x. Epub 2010 Oct 11.

Abstract

The role of intereukin-1 (IL-1) in mortality caused by endotoxaemia remains controversial. While IL-1 receptor antagonist (IL-1Ra) protects mice from lethal endotoxaemia, mice deficient in IL-1β (IL-1β⁻( /)⁻) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies. Mice deficient in IL-1α, IL-1β or IL-1R type I were injected intraperitoneally with Escherichia coli or Salmonella typhimurium LPS. Survival of the mice was examined and compared with C57/Bl6 wild-type mice. In addition, serum cytokine concentrations were determined after LPS challenge and in vitro cytokine production by peritoneal macrophages was analysed. Clearance of radioactive IL-1α was examined in IL-1α⁻(/)⁻ and wild-type mice. IL-1β⁻(/)⁻ mice were normally susceptible to endotoxaemia and cytokine production did not differ from that in control mice. Surprisingly, LPS mortality in IL-1α⁻(/)⁻ mice was significantly greater than that in control mice, accompanied by higher interferon-γ release. These effects were mediated by a distorted homeostasis of IL-1RI receptors, as shown by a strongly delayed clearance of IL-1α. In contrast to the IL-1α⁻(/)⁻ and IL-1β⁻(/)⁻ mice, IL-1RI⁻(/)⁻ mice were completely resistant to high doses of LPS. In conclusion, IL-1RI-mediated signals are crucial in mediating mortality occurring as a result of lethal endotoxaemia. Investigation of IL-1-mediated pathways in IL-1 knock-out mice is complicated by a distorted homeostasis of IL-1Rs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endotoxemia / immunology*
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1alpha / deficiency*
  • Interleukin-1alpha / immunology
  • Interleukin-1beta / deficiency*
  • Interleukin-1beta / immunology
  • Kaplan-Meier Estimate
  • Lipopolysaccharides / administration & dosage
  • Macrophages, Peritoneal / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / deficiency*
  • Receptors, Interleukin-1 / immunology
  • Specific Pathogen-Free Organisms

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1alpha
  • Interleukin-1beta
  • Lipopolysaccharides
  • Receptors, Interleukin-1