Lack of Glycoprotein 130/Signal Transducer and Activator of Transcription 3-Mediated Signaling in Hepatocytes Enhances Chronic Liver Injury and Fibrosis Progression in a Model of Sclerosing Cholangitis

Abstract

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

Nrf2 Induces Interleukin-6 (IL-6) Expression via an Antioxidant Response Element within the IL-6 Promoter

“…4B). We next tested IL-6 expression in a mouse model for steatohepatitis where IL-6 is up-regulated and has a well known protective function (14). As expected, the expression of IL-6 was up-regulated in DDC-treated wild-type mice.…”

“…DDC Induced in Vivo IL6 Expression-It is known that the IL-6 production is elevated in the liver of DDC-treated mice (14). To explore if Nrf2 is the transcription factor inducing the IL-6 up-regulation under these conditions we treated Nrf2-knock-out and wild type mice with DDC for 3 weeks.…”

“…Oxidative stress is one main feature in nonalcoholic steatohepatitis and its mouse model DDC feeding (12,13 Plum et al (14) showed a protective role of the IL-6/gp-130 pathway in this cholestatic hepatitis model. In this study we show that Nrf2 binds to ARE within the promoter region of the IL-6 gene thus highly activating IL-6 transcription.…”

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

“…In a similar model, hepcidin was shown to exert its intrinsic antiinflammatory effect through the phosphorylation of Stat3 (33). While this could be relevant to liver transplantation given the immunoregulatory function of Stat3 (34)(35)(36)(37), the role of hepcidin and iron metabolism in models of immune-mediated liver diseases has yet to be investigated. Ours is therefore the first report to our knowledge indicating that modulation of hepcidin expression and redistribution of intra-graft iron stores could be involved in the capacity of the liver allograft to restrain alloreactive immune responses.…”

Lack of hepatic c-Met and gp130 expression is associated with an impaired antibacterial response and higher lethality after bile duct ligation

“…Previous studies demonstrated that besides inflammatory cytokines (IL-6 13 and TNF-a 20 ) also the growth factor HGF 14,15,21 was upregulated during cholestatic liver injury. Moreover, both IL-6/gp130 and HGF/c-Met controlled pathways were independently shown to limit the progression of experimentally induced cholestasis 15,22 in animal models. Here, we demonstrate that deletion of both gp130 and c-Met signalling in hepatocytes leads to an additive degree of parenchymal and biliary tissue injury (Figures 1b, c and 2c) and a dysregulation of the hepatic innate immune response.…”