Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1alpha, IL-1beta or IL-1 receptor type I.

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-1beta (IL-1beta( /)) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies. Mice deficient in IL-1alpha, IL-1beta 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-1alpha was examined in IL-1alpha(/) and wild-type mice. IL-1beta(/) mice were normally susceptible to endotoxaemia and cytokine production did not differ from that in control mice. Surprisingly, LPS mortality in IL-1alpha(/) mice was significantly greater than that in control mice, accompanied by higher interferon-gamma release. These effects were mediated by a distorted homeostasis of IL-1RI receptors, as shown by a strongly delayed clearance of IL-1alpha. In contrast to the IL-1alpha(/) and IL-1beta(/) 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.