Kupffer cells abrogate cholestatic liver injury in mice.
OBJECTIVE
Biliary obstruction and cholestasis can cause hepatocellular apoptosis and necrosis. Ligation of the common bile duct in mice provides an excellent model in which to study the underlying mechanisms. Kupffer cells play a key role in modulating the inflammatory response observed in most animal models of liver injury. This study was performed to determine the role of Kupffer cells in the injury attending cholestasis.


METHODS
Mice were not treated or were rendered Kupffer 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, interleukin-6 (IL-6)-deficient and tumor necrosis factor-receptor-deficient mice underwent bile duct ligation (BDL) or sham operations.


RESULTS
Serum alanine transaminase levels were increased in all BDL mice at 3 days after surgery, but were significantly higher in IL-6-deficient mice or mice rendered Kupffer cell-depleted before ligation. Histologic examination of BDL livers showed portal inflammation, neutrophil infiltration, bile duct proliferation, and hepatocellular necrosis. Photoimage analyses confirmed more necrosis in the livers of Kupffer cell-depleted and IL-6-deficient animals. Purified Kupffer cells derived from BDL animals produced more IL-6 in culture. Similarly, Kupffer cells obtained by laser capture microdissection from the livers of BDL mice expressed increased levels of IL-6 messenger RNA. Recombinant mouse IL-6 administered 1 hour before BDL completely reversed the increased liver damage assessed otherwise in Kupffer cell-depleted mice.


CONCLUSIONS
These findings indicate that Kupffer cells abrogate cholestatic liver injury by cytokine-dependent mechanisms that include the production of IL-6.
Gehring
Stephan
S
Department of Medicine, Rhode Island and Hasbro Children's Hospitals, Brown Medical School, Providence, Rhode Island, USA.
Dickson
Elizabeth M
EM
San Martin
Maryann E
ME
van Rooijen
Nico
N
Papa
Elaine F
EF
Harty
Mark W
MW
Tracy
Thomas F
TF
Gregory
Stephen H
SH
D000818:Animals; D002779:Cholestasis / Q000473:pathology*; D004002:Clodronic Acid / Q000008:administration & dosage; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007728:Kupffer Cells / Q000502:physiology*; D008081:Liposomes; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection; D009336:Necrosis; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007375:Interleukin-1; D015850:Interleukin-6; D008081:Liposomes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid