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Published ahead of print on November 6, 2003, doi:10.1164/rccm.200303-311OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 413-420, (2004)
© 2004 American Thoracic Society

Cholestatic Interleukin-6–Deficient Mice Succumb to Endotoxin-induced Liver Injury and Pulmonary Inflammation

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

Departments of Surgery, Experimental Internal Medicine, Cell Biology and Histology, and Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Miguel E. Sewnath, M.D., P.O. Box 22700, G4-Suite 126, Department of Surgery, Academic Medical Center, 1100 DE Amsterdam, The Netherlands. E-mail: m.e.sewnath{at}olvg.nl

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.

Key Words: acute respiratory distress syndrome • bile duct obstruction • cytokines • knockout mice • sepsis




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