title: RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation.
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 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.
authors: Department of Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
authors: Mihael
authors: M
authors: Vucur
authors: Florian
authors: F
authors: Reisinger
authors: Jérémie
authors: J
authors: Gautheron
authors: Joern
authors: J
authors: Janssen
authors: Christoph
authors: C
authors: Roderburg
authors: David Vargas
authors: DV
authors: Cardenas
authors: Karina
authors: K
authors: Kreggenwinkel
authors: Christiane
authors: C
authors: Koppe
authors: Linda
authors: L
authors: Hammerich
authors: Razq
authors: R
authors: Hakem
authors: Kristian
authors: K
authors: Unger
authors: Achim
authors: A
authors: Weber
authors: Nikolaus
authors: N
authors: Gassler
authors: Mark
authors: M
authors: Luedde
authors: Norbert
authors: N
authors: Frey
authors: Ulf Peter
authors: UP
authors: Neumann
authors: Frank
authors: F
authors: Tacke
authors: Christian
authors: C
authors: Trautwein
authors: Mathias
authors: M
authors: Heikenwalder
authors: Tom
authors: T
authors: Luedde
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007565:Jaundice / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D048670:MAP Kinase Kinase 4; D053181:Caspase 8