Endogenous interferon gamma protects against cholestatic liver injury in mice

Cholestatic patients suffer from high perioperative morbidity and mortality, but the pathophysiology is still unknown. Interferon gamma (IFN-gamma) may play a role during cholestasis. Therefore, bile duct ligation (BDL) was induced in IFN-gamma alpha-chain receptor-deficient (IFN-gammaR(1)-/-) and wild-type (IFN-gammaR(1)+/+) mice. BDL elicited increased IFN-gamma messenger RNA and protein levels in the liver. One week after BDL, IFN-gammaR(1)+/+ mice showed less severe jaundice and liver injury than IFN-gammaR(1)-/- mice, as reflected by lower bilirubin and liver enzyme levels. In accordance, livers of IFN-gammaR(1)+/+ mice displayed smaller areas of necrosis by two-thirds than IFN-gammaR(1)-/- mice on histopathologic examination (P <.05), whereas mitotic activity and proliferating cell nuclear antigen (PCNA) labeling index was more than twice as high in IFN-gammaR(1)+/+ mice (P <.05). Livers of IFN-gammaR(1)+/+ mice displayed higher rates of apoptosis as indicated by DNA fragmentation rate, the number of apoptotic bodies, and poly ADP-ribose polymerase (PARP) immunostaining. BDL was not associated with lethality in IFN-gammaR(1)+/+ mice; IFN-gammaR(1)-/- mice, however, died from 10 days onward and survival after 2 weeks was 62% (10 of 16). In conclusion, these data suggest that IFN-gamma protects against liver injury during extrahepatic cholestasis by stimulation of apoptosis and subsequent proliferation of hepatocytes, leading to elegant removal of damaged hepatocytes, thus preventing necrosis and concomitant inflammatory responses.