title: Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin.
abstract: Cholestatic liver injury is associated with an increased susceptibility toward endotoxin-induced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R(-/-)) mice, which are unresponsive to IL-1alpha and IL-1beta, and normal IL-1R(+/+) mice. Bdl elicited increases in hepatic IL-1alpha and IL-1beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R(-/-) and IL-1R(+/+) mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in sham-operated IL-1R(-/-) and IL-1R(+/+) mice were largely similar, but cholestatic IL-1R(-/-) mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1alpha and IL-1beta are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl.
authors.affiliation: Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.e.sewnath@amc.uva.nl
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Sewnath
authors.forename: Tom
authors.initials: T
authors.lastname: Van Der Poll
authors.forename: Fiebo J W
authors.initials: FJ
authors.lastname: Ten Kate
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: Van Noorden
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Gouma
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000502:physiology* / Q000601:surgery; D056486:Chemical and Drug Induced Liver Injury; D002780:Cholestasis, Intrahepatic / Q000209:etiology; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000633:toxicity*; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology; D008026:Ligation; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D053573:Receptors, Interleukin-1 Type I
chemical_list: D016207:Cytokines; D004731:Endotoxins; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I