Prevention of hepatic fibrosis in nonobese diabetic mice: a critical role for interferon-gamma.
OBJECTIVE
Nonobese diabetic (NOD) mice, a model of type I diabetes mellitus, harbor certain unique defects in their immune system. The aim of this study was to investigate how NOD mice show hepatic injury and subsequent fibrogenic responses.


METHODS
Hepatic fibrosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN), and assessed biochemically and histologically. Expressions of cytokine messenger RNA (mRNA) in the liver were determined.


RESULTS
In a model of liver cirrhosis induced by dimethylnitrosamine (DMN), we found that NOD mice had lower levels of hepatic fibrosis and better survival than control ICR mice. The resistance to DMN-induced lethality in NOD mice was independent of apoptosis and necrosis of hepatocytes, but apparently due to the prevention of hepatic fibrosis. We also found increased inductions of interferon-gamma (IFN-gamma) mRNA in the liver of NOD mice and of intracellular IFN-gamma from intrahepatic T cells following DMN administration. Treatment with neutralizing anti-IFN-gamma-antibody cancelled the inhibition of hepatic fibrosis in NOD mice.


CONCLUSIONS
These results suggest that IFN-gamma is effective for inhibiting hepatic fibrosis and that genetic host factors may be important in determining differential responses to injury.
Mukai
Tsuyoshi
T
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
Nagaki
Masahito
M
Imose
Motoaki
M
Kimura
Kiminori
K
Satake
Shinichi
S
Takai
Shinji
S
Moriwaki
Hisataka
H
D000818:Animals; D004128:Dimethylnitrosamine; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD
D007371:Interferon-gamma; D004128:Dimethylnitrosamine