title: Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1β 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-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.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Center, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Frank L
authors.initials: FL
authors.lastname: Van De Veerdonk
authors.forename: Alieke G
authors.initials: AG
authors.lastname: Vonk
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Monique
authors.initials: M
authors.lastname: Keuter
authors.forename: Giamilla
authors.initials: G
authors.lastname: Fantuzzi
authors.forename: Ineke
authors.initials: I
authors.lastname: Verschueren
authors.forename: Tom
authors.initials: T
authors.lastname: Van Der Poll
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Jos W M
authors.initials: JW
authors.lastname: Van Der Meer
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000172:deficiency* / Q000276:immunology; D053583:Interleukin-1beta / Q000172:deficiency* / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000008:administration & dosage; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology; D013047:Specific Pathogen-Free Organisms
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1