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Vucur, M.* ; Reisinger, F. ; Gautheron, J.* ; Janssen, J.* ; Roderburg, C.* ; Cardenas, D.V.* ; Kreggenwinkel, K.* ; Koppe, C.* ; Hammerich, L.* ; Hakem, R.* ; Unger, K. ; Weber, A.* ; Gassler, N.* ; Luedde, M.* ; Frey, N.* ; Neumann, U.P.* ; Tacke, F.* ; Trautwein, C.* ; Heikenwälder, M. ; Luedde, T.*

RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation.

Cell Rep. 4, 776-790 (2013)
Verlagsversion Volltext DOI
Open Access Gold
Creative Commons Lizenzvertrag
For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nf-kappa-b ; Hepatocellular-carcinoma ; Ikk-beta ; Chemical Hepatocarcinogenesis ; Nonalcoholic Steatohepatitis ; Programmed Necrosis ; Liver-cancer ; Tnf-alpha ; Tak1 ; Fibrosis
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 4, Heft: 4, Seiten: 776-790 Artikelnummer: , Supplement: ,
Verlag Cell Press
Begutachtungsstatus Peer reviewed