Cholestatic interleukin-6-deficient mice succumb to endotoxin-induced liver injury and pulmonary inflammation.
Circulating and hepatic interleukin (IL)-6 levels are strongly increased during clinical and experimental cholestasis. Cholestatic liver injury is associated with increased susceptibility to endotoxin-induced toxicity. To determine the role of IL-6 herein, extrahepatic cholestasis was induced by bile duct ligation (BDL) in IL-6-gene deficient (IL-6(-/-)) and normal (IL-6(+/+)) mice. BDL elicited increased levels of hepatic IL-6 mRNA and protein in normal mice. Hepatocellular injury 2 weeks after BDL was similar in IL-6(-/-) and IL-6(+/+) mice as demonstrated by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice 2 weeks after BDL was associated with enhanced cytokine release, severe liver damage, and death when compared with sham-operated mice. Effects of endotoxin were largely similar in sham-operated IL-6(-/-) and IL-6(+/+) mice, but cholestatic IL-6(-/-) mice were more susceptible to the toxic effects of endotoxin, as reflected by increased cytokine release, more profound liver injury and lung inflammation, and higher mortality. Although endogenous IL-6 is not important in the development of liver injury after experimentally induced obstructive jaundice, this cytokine plays an important role in decreasing hypersensitivity to endotoxin in cholestatic mice.
Sewnath
Miguel E
ME
Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.e.sewnath@olvg.nl
van der Poll
Tom
T
van Noorden
Cornelis J F
CJ
ten Kate
Fiebo J W
FJ
Gouma
Dirk J
DJ
D000818:Animals; D001483:Base Sequence; D001707:Biopsy, Needle; D002779:Cholestasis / Q000401:mortality* / Q000473:pathology*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000494:pharmacology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011014:Pneumonia / Q000401:mortality* / Q000473:pathology*; D011336:Probability; D012313:RNA / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015996:Survival Rate
D004731:Endotoxins; D015850:Interleukin-6; D012313:RNA