Methods:

Mice were not treated or renderedKupffer cell-depleted by intravenous inoculation of multilamellar liposome-encapsulated dichloromethylene diphosphonate, the common bile duct was ligated and divided; sham-operated animals served as controls. Similarly, IL-6-deficient and TNF receptor-deficient mice underwent BDLor sham operations.

Results:

Serum ALT levels were elevated in all BDL mice at 3 days post-surgery, but were significantly higher in IL-6-deficient mice or mice rendered Kupffer cell-depleted prior to ligation. Histologic examination of BDL livers revealed portal inflammation, neutrophil infiltration, bileduct proliferation and hepatocellular necrosis. Photo image analyses confirmed more necrosis in the livers of Kupffer cell-depleted and of IL-6-deficient animals. Purified Kupffer cells derived from BDL animals produced more interleukin-6 (IL-6) in culture. Similarly, Kupffer cells obtained by laser capture microdissection from the livers of BDL mice expressed elevated levels of IL-6 mRNA. Recombinant mouse IL-6 administered 1 hour prior to BDL completely reversed the increased liverdamage assessed otherwise in Kupffer cell-depleted mice.

Conclusion:

These findings indicate that Kupffer cells abrogate cholestatic liver injury by cytokine-dependent mechanisms that include the production of IL-6.