The 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model leads to chronic cholestatic liver injury and therefore resembles human diseases such as sclerosing cholangitis and forms of metabolic liver diseases. The role of the interleukin-6/glycoprotein 130 (gp130) system in this context is still undefined. Therefore, conditional gp130 knockout and knockin mice were used to achieve hepatocyte-specific deletions of gp130 (gp130 ⌬hepa ), gp130-dependent ras (gp130 ⌬hepaRas ), and signal transducer and activator of transcription (STAT) (gp130 ⌬hepaSTAT ) activation. These mice were treated with a DDC-containing diet and analyzed over time. Mice deficient in hepatic gp130 and STAT signaling showed increased and earlier mortality than wild-type and gp130⌬hepaRas animals. Over time, significantly more apoptosis and cholestasis became evident in gp130 ⌬hepa and gp130 ⌬hepaSTAT mice. These mice also displayed increased tumor necrosis factor-␣ expression, a diminished acute-phase response (lack of STAT3 and serum amyloid A activation), and enhanced immune cell infiltration in the liver. These were associated with stronger periportal oval cell activation. In addition, DDC treatment in gp130 ⌬hepa and gp130 Liver remodeling and fibrosis progression are often the result of an insufficient response of hepatocytes and biliary epithelial cells to different forms of chronic liver injury. A complex network of different liver and immune cells activates cytokines and growth factors, which trigger myofibroblasts to produce extracellular matrix proteins including collagen. Feeding mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) is a well established model to study such complex interactions in a highly relevant model of chronic cholestatic liver injury resembling certain metabolic, toxic, and cholestatic chronic liver diseases.1 Moreover, the model leads to a strong fibrotic response in the liver and can enhance the tumorigenic potential of proto-oncogenes.2 The model has also been used to study mechanisms of oval cell activation and proliferation. 3 The cholestatic phenotype of the model and its underlying pathobiology have only recently been elucidated in more detail.1 DDC feeding induces sclerosing cholangitisSupported by the Deutsche Forschungsgemeinschaft (grants 661/4-1 to K.L.S. and TRR57 to C.T.) and by the START program
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