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 inj...