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

Mihael Vucur, Florian Reisinger, Jérémie Gautheron, Joern Janssen, Christoph Roderburg, David Vargas Cardenas, Karina Kreggenwinkel, Christiane Koppe, Linda Hammerich, Razq Hakem, Kristian Unger, Achim Weber, Nikolaus Gassler, Mark Luedde, Norbert Frey, Ulf Peter Neumann, Frank Tacke, Christian Trautwein, Mathias Heikenwalder, Tom Luedde

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

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 inhibitsintrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance totumor-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

Original languageEnglish
Pages (from-to)776-790
Number of pages15
JournalCell Reports
Volume4
Issue number4
DOIs
StatePublished - 29 Aug 2013
Externally publishedYes

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