title: Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury.
abstract: OBJECTIVE
  Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signalling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMO(Δhepa)), a genetic model of chronic inflammatory liver injury.
  
  
  METHODS
  We generated Jnk1(-/-)/NEMO(Δhepa) and Jnk2(-/-)/NEMO(Δhepa) mice by crossing NEMO(Δhepa) mice with Jnk1 and Jnk2 global deficient animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analysed the expression of NEMO and p-JNK in human diseased-livers.
  
  
  RESULTS
  Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMO(Δhepa) mice. Conversely, Jnk2(-/-)/NEMO(Δhepa) displayed hepatic inflammation. By using bone marrow transfer, we observed that Jnk1 in haematopoietic cells had an impact on the progression of chronic liver disease in NEMO(Δhepa) livers. These findings are of clinical relevance since NEMO expression was downregulated in hepatocytes of patients with HCC whereas NEMO and p-JNK were expressed in a large amount of infiltrating cells.
  
  
  CONCLUSIONS
  A synergistic function of Jnk1 in haematopoietic cells and hepatocytes might be relevant for the development of chronic liver injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Nevzorova
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hatting
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Malika
authors.initials: M
authors.lastname: Al Masaoudi
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Verdier
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Frederik M
authors.initials: FM
authors.lastname: Schaefer
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hermanns
authors.affiliation: Division of Nutrition, Metabolism & Genomics, Wageningen University, Wageningen, The Netherlands.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.affiliation: Department of Experimental Molecular Imaging, University Hospital, RWTH Aachen, Aachen, Germany; Department of Diagnostic and Interventional Neuroradiology, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grouls
authors.affiliation: Institute of Pathology, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Department of Experimental Molecular Imaging, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Division of Nutrition, Metabolism & Genomics, Wageningen University, Wageningen, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Muller
authors.affiliation: Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany. Electronic address: ctrautwein@ukaachen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D004273:DNA, Neoplasm; C541074:JKAMP protein, human; D008562:Membrane Glycoproteins
keywords: Apoptosis; HCC; IKKγ/NEMO; Jnk1; Jnk2; Necrosis