title: Lack of gp130 expression in hepatocytes promotes liver injury.
abstract: OBJECTIVE
  Interleukin 6 (IL-6) contributes via its signal transducer gp130 to the acute phase response (APR) in hepatocytes. Recent studies indicated that IL-6 is involved in the regulation of different pathophysiologic conditions of the liver. To define the IL-6-dependent intracellular pathways more specifically, we generated a hepatocyte-specific gp130 knockout mouse.
  
  
  METHODS
  Hepatocyte-specific gp130-deficient mice were generated using the Cre-loxP system. Expression of the Cre recombinase was under the control of a hepatocyte-specific control element. Adult mice were challenged with IL-6, oncostatin M (OSM), and LPS.
  
  
  RESULTS
  Cre expression started at day 10.5 postconception, and a complete deletion of gp130 in hepatocytes was found at day 14 during liver development. The adult liver of these mice showed no abnormalities; however, after IL-6 and OSM stimulation, gp130-dependent pathways (STAT3, APR gene expression) were completely blocked in the liver of these animals. Additionally, challenging hepatocyte-specific gp130 knockout animals with lipopolysaccharides (LPS) lead to an onset of acute liver injury with an increase of hepatocyte apoptosis associated with elevated tumor necrosis factor alpha (TNF-alpha) serum levels and reduced nuclear factor kappaB (NF-kappaB) activation in hepatocytes.
  
  
  CONCLUSIONS
  Our findings demonstrate that gp130 is of minor relevance for embryonal development of hepatocytes. However, the molecule has an essential role in controlling acute phase gene expression and provides hepatocellular protection after LPS challenge.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
authors.forename: Torsten
authors.initials: T
authors.lastname: Wüstefeld
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Kallen
authors.forename: Francois
authors.initials: F
authors.lastname: Tronche
authors.forename: Ullrich A K
authors.initials: UA
authors.lastname: Betz
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D017209:Apoptosis; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000737:chemistry* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000196:embryology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130