The development and compensation of biliary cirrhosis in interleukin-6-deficient mice.
In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6(-/-)) and wild-type control (IL-6(+/+)) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6(-/-) mice develop significantly higher total serum bilirubin levels (23.2 +/- 2.3 versus 14.9 +/- 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 +/- 4.0% versus 9.2 +/- 1.8%; P < 0.002), and the majority (15/18) show "black" gallbladder bile, compared to IL-6(+/+) mice (5/16; P < 0.003). The IL-6(-/-) mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6(+/+) mice. Moreover, IL-6(-/-) mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6(+/+) controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6(-/-) mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6(+/+) mice. Daily treatment with exogenous recombinant IL-6 for 3-6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6(-/-) mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury.
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Thomas E. Starzl Transplantation Institute, Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Sakamoto
T
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Tsuji
H
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Lunz
J G
JG
Murase
N
N
Fung
J J
JJ
Demetris
A J
AJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis; D001646:Bile / Q000737:chemistry; D001652:Bile Ducts / Q000601:surgery; D001663:Bilirubin / Q000097:blood; D001835:Body Weight; D002455:Cell Division; D050822:Cytokine Receptor gp130; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D008026:Ligation / Q000009:adverse effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis
D015703:Antigens, CD; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130; D000410:Alanine Transaminase; D001663:Bilirubin