Z Gastroenterol 2011; 49 - P1_49
DOI: 10.1055/s-0030-1269499

TRAIL and TNFR1-dependent pathways and their role for progression of Nemo-dependent hepatitis

A Singh 1, FJ Cubero 1, E Borkham-Kamphorst 2, M Al-Masaoudi 1, C Liedtke 1, T Luedde 1, R Weiskirchen 2, M Heikenwälder, 3, C Trautwein 1
  • 1Dept. of Internal Medicine III (Hepatology, Gastroenterology and Metabolism), Universitätsklinikum Aachen, Aachen
  • 2Institut für Klinische Chemie und Pathobiochemie, Universitätsklinikum der RWTH Aachen, Aachen
  • 3Institute of Neuropathology, Zürich, Switzerland

Hepatocyte-specific NEMO knockout mice (NemoΔhepa) show that the IκB kinase subunit NEMO/IKKγ is essential for activating the transcription factor NF-κB, which regulates cellular responses during inflammation, cell proliferation and apoptosis. Therefore we aimed to better characterise the protective pathways in death receptor-mediated hepatocyte apoptosis in NemoΔhepa animals. We generated NemoΔhepaTRAIL-/-, NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- animals and analyzed the consequences compared to NemoΔhepa animals. NemoΔhepaTRAIL-/- like NemoΔhepa mice developed a phenotype characterized by apoptosis, proliferation, steatohepatitis, fibrosis, and the appearance of first liver nodules at 8 weeks which was ameliorated in NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- livers. Hepatocyte apoptosis was significantly increased in NemoΔhepa and NemoΔhepaTRAIL-/- mice while NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- showed predominantly necrosis. This phenotype was accompanied by a strong reduction in pJNK levels in NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- compared with NemoΔhepa and NemoΔhepaTRAIL-/- mice. Additionally, cell cycle parameters were significantly less activated in NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- livers. This was further confirmed in primary hepatocytes. NemoΔhepaTNFR1-/--derived hepatocytes showed increased survival and less apoptosis compared to NemoΔhepa hepatocytes. To further support the functional role of TNFR1 signalling in NemoΔhepa animals, we performed LPS stimulation experiments. Here NemoΔhepaTNFR1-/- and NemoΔhepaTRAIL-/-TNFR1-/- animals were protected, while both NemoΔhepa and NemoΔhepaTRAIL-/- animals were hypersensitive to the challenge as evidenced by transaminases levels and markers of apoptosis. Our present data using double and triple knockout animals demonstrate that the death receptor TNFR1 in contrast to TRAIL is essential in determining the long term prognosis of NemoΔhepa animals.

Apoptosis - Cell cycle - HCC - NF-kB - TNFR - Trail