title: Cooperative role of lymphotoxin β receptor and tumor necrosis factor receptor p55 in murine liver regeneration.
abstract: OBJECTIVE
  The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-β receptor (LTβR), a core member of the tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) superfamily is known to play an important role in this process. However, the function of LTβR during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized.
  
  
  METHODS
  LTβR(-/-) mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed.
  
  
  RESULTS
  LTβR(-/-) deficient mice suffered from increased and prolonged liver tissue damage after 70% hepatectomy, accompanied by deregulated bile acid homeostasis. Pronounced differences in the expression patterns of genes relevant for bile acid synthesis and recirculation were observed. LTβR and TNFRp55 share downstream signalling elements. Therefore, LTβR(-/-) mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LTβR signalling leads to complete failure of liver regeneration resulting in death within 24 to 48h after PHx. Transcriptome analysis revealed a marked disparity in gene expression programs in livers of LTβR(-/-) and etanercept-treated LTβR(-/-) vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene.
  
  
  CONCLUSIONS
  LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signalling renders liver regeneration impossible.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Sorg
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany; Molecular Medicine II, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Behnke
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Degrandi
authors.affiliation: Department of Internal Medicine, Gastroenterology, Hepatology and Infectious Diseases, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Reich
authors.affiliation: Department of Internal Medicine, Gastroenterology, Hepatology and Infectious Diseases, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Diran
authors.initials: D
authors.lastname: Herebian
authors.affiliation: Center for Biological and Medical Research, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Deenen
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Center for Biological and Medical Research, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.affiliation: Institute of Pathology, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Gabbert
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Department of Internal Medicine, Gastroenterology, Hepatology and Infectious Diseases, University Children's Hospital, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany. Electronic address: Klaus.pfeffer@hhu.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics*; D053259:Lymphotoxin beta Receptor / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000235:genetics*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D053259:Lymphotoxin beta Receptor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D004247:DNA
keywords: Bile acids; Etanercept; Mug2; Partial hepatectomy; Transcriptome analysis