title: Induction of lipocalin-2 expression in acute and chronic experimental liver injury moderated by pro-inflammatory cytokines interleukin-1β through nuclear factor-κB activation.
abstract: BACKGROUND
  Lipocalin-2 (LCN2) belongs to the lipocalin superfamily, sharing a barrel-shaped tertiary structure with a hydrophobic pocket and an ability to bind lipophilic molecules. LCN2 has recently emerged as an important modulator of cellular homeostasis in several organs, i.e. heart, lung and kidney, but little is known about the expression of LCN2 in acute and chronic liver injury.
  
  
  OBJECTIVE
  In this study, we wanted to analyse the expression and regulation of LCN2 in models of acute and chronic experimental liver injury.
  
  
  METHODS
  We analysed LCN2 expression in livers of rats subjected to bile duct ligation or repeated doses of carbon tetrachloride and tested the impact of various pro-inflammatory cytokines in cultured primary liver cells.
  
  
  RESULTS
  By using primary cultures of hepatic stellate cells and hepatocytes isolated from normal and injured rat livers, we found a significant LCN2 expression in early hepatic stellate cell cultures, a lower expression in fully transdifferentiated myofibroblasts and no expression in freshly isolated hepatocytes. However, LCN2 expression and secretion in hepatocytes increased dramatically during culturing. In addition, chronic in vivo liver injury resulting from both bile duct ligation and repeated application of carbon tetrachloride resulted in rapid and well-sustained induction of LCN2 expression. Immunohistochemistry and primary liver cell isolation identified injured hepatocytes as the main source of LCN2 production. LCN2 is strongly induced in both primary hepatocytes and immortalized hepatocellular carcinoma cell line HepG2 by the pro-inflammatory cytokine interleukin-1β via nuclear factor-κB activation, but not by the profibrotic cytokines platelet-derived growth factor and transforming growth factor-β.
  
  
  CONCLUSIONS
  LCN2 expression shows clear correlation to liver damage and resulting inflammatory responses, rather than to the degree of liver fibrosis, which in fact may imply a distinct diagnostic value as an early biomarker of liver inflammation.
authors: Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University Hospital, Aachen, Germany.
authors: Erawan
authors: E
authors: Borkham-Kamphorst
authors: Falko
authors: F
authors: Drews
authors: Ralf
authors: R
authors: Weiskirchen
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D058750:Epithelial-Mesenchymal Transition; D017930:Genes, Reporter; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006505:Hepatitis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008026:Ligation; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D058628:Myofibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C489506:LCN2 protein, human; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D002251:Carbon Tetrachloride