Z Gastroenterol 2009; 47 - V1_01
DOI: 10.1055/s-0029-1191752

Hepatocyte specific NEMO deletion promotes NK/NKT cell dependent liver damage

N Beraza 1, Y Malato 1, LE Sander 1, M Al-Masaoudi 1, J Freimuth 1, D Riethmacher 2, T Roskams 3, C Liedtke 1, C Trautwein 1
  • 1Medizinische Klinik III, Universitätsklinikum Aachen, RWTH Aachen
  • 2Human Genetics Division, Southampton University School of Medicine
  • 3Department of Pathology, Catholic University of Leuven

The nuclear factor kappa B (NF-κB) is essential in the regulation of apoptosis, inflammation, chronic liver disease and progression of cancer. NF-κB is activated after phosphorylation of IκB by the IKK complex. The IKK complex consists in two catalytic subunits IKKa/1 and IKKb/2 and a regulatory subunit IKKγ/NEMO. We generated hepatocyte specific NEMO deleted mice (NEMOΔhepa) that exhibit chronic inflammation, steatohepatitis and HCC development. NEMOΔhepa mice are highly susceptible to TNF mediated liver damage, although the impact of other TNF-family of cytokines and their implication in the development of the damaging phenotype in NEMOΔhepa mice remains unknown.

We show that NEMOΔhepa mice are resistant to Jo2 mediated apoptosis as hepatocyte NEMO deletion leads to impaired expression of Fas in hepatocytes. On the contrary, TRAILR2/DR5 was strongly up-regulated in NEMOΔhepa mice and low doses of TRAIL promoted strong liver damage in these animals. NK cells are the main producers of TRAIL and we found these cells to be strongly activated in livers from NEMOΔhepa mice. Interestingly, depletion of NK1.1+cells significantly improved liver histology in NEMOΔhepa mice. Furthermore, hepatocyte specific NEMO deletion strongly sensitized the liver to Concanavalin A (ConA). The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was confirmed by NK1.1+cell depletion that significantly ameliorated liver damage. In this line, adoptive transfer of TRAIL-/- mononuclear cells (MNCs) into NK/NKT cell depleted animals preserved the protective effect in NEMODhepa livers against ConA, while TRAIL+/+ MNCs restored liver injury.

Our results uncover an essential mechanism of NEMO to protect the liver by preventing NK cell mediated tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.

NFkappaB - NK/NKT cells - TRAIL - hepatitis