title: Keratins 8 and 18 are type II acute-phase responsive genes overexpressed in human liver disease.
abstract: OBJECTIVE
  Keratins (Ks) 7, 8, 18 and 19 constitute important markers and modifiers of liver disease. In mice, K8 and K18 are stress inducible and a dysregulated K8 > K18 stoichiometry predisposes to formation of Mallory-Denk bodies (MDBs), i.e. aggregates characteristic of chronic liver disorders such as alcoholic liver disease (ALD). In our study, we analyse the expression and the regulation of keratins in context of human liver disease.
  
  
  METHODS
  K7, K8, K18 and K19 mRNA levels were determined in liver biopsies from patients with ALD, non-alcoholic steatohepatitis (NASH), chronic hepatitis B (HBV), hepatitis C (HCV) and from control subjects. HepG2 and Hep3B cells were treated with IL-1β, IL-6 and TNF-α. Mice were injected with turpentine, an established IL-6 inducer.
  
  
  RESULTS
  K7, K8 and K18 were 1.5- to 3-fold upregulated in livers of ALD and HCV patients with a more active disease, but not in HBV/NASH subjects, while K19 was significantly elevated in all analysed disorders. K8 and K18 expression displayed a strong correlation (r = 0.89), but dysregulated levels with the K8 > K18 state were seen in ALD. All keratins were overexpressed in subjects with moderate vs. minimal inflammation, while K7, K8 and K18 were upregulated in patients with advanced liver fibrosis. In HepG2/Hep3B cells, IL-6 treatment but not IL-1β or TNF-α significantly increased K8 and K18 expression and elevated K18 levels were seen after turpentine injection.
  
  
  CONCLUSIONS
  Keratins represent type II acute-phase responsive genes overexpressed in specific human liver disorders. A K8 > K18 state occurs in ALD and predisposes to MDB formation.
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany; IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Nurdan
authors.initials: N
authors.lastname: Guldiken
authors.forename: Valentyn
authors.initials: V
authors.lastname: Usachov
authors.forename: Kateryna
authors.initials: K
authors.lastname: Levada
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053538:Keratin-18 / Q000235:genetics*; D053533:Keratin-8 / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014425:Turpentine; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D018836:Inflammation Mediators; C488421:KRT18 protein, human; C426203:KRT8 protein, human; D053538:Keratin-18; D053533:Keratin-8; C486595:Krt8 protein, mouse; D012333:RNA, Messenger; D014425:Turpentine
keywords: alcoholic liver disease; hepatitis B; hepatitis C; interleukin 6; non-alcoholic steatohepatitis