Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin

Miguel E. Sewnath, Tom van der Poll, Fiebo J. W. ten Kate, Cornelis J. F. van Noorden, Dirk J. Gouma

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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-IR-/-) mice, which are unresponsive to IL-1 alpha and IL-1 beta, and normal 1L-1R(+/+) mice. Bdl elicited increases in hepatic IL-1 alpha and IL-1 beta messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-IR-/- 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-1 alpha and IL-1 beta 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
Original languageEnglish
Pages (from-to)149-158
JournalHepatology (Baltimore, Md.)
Issue number1
Publication statusPublished - 2002

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