title: Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease.
abstract: Keratins (K) constitute the epithelial intermediate filaments. Among them, K7/K19 are widely used markers of the regenerative liver response termed ductular reaction (DR) that consists of activated biliary epithelial cells (BECs) and hepatic progenitor cells (HPCs) and correlates with liver disease severity. In the present study we aimed to characterize K23 in the liver.
  
  
  
  We analyzed the expression and localization of K23 in the digestive system under basal conditions as well as in various human and mouse liver diseases/stress models. Cell culture studies were used to study factors regulating K23 expression.
  
  
  
  In untreated mice, K23 was restricted to biliary epithelia. It was (together with K7/K19) markedly upregulated in three different DR/cholestatic injury models, i.e., multidrug resistance protein 2 (Mdr2) knockouts, animals treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine or subjected to bile duct ligation. K23 levels correlated with the DR marker Fn14 and immunofluorescence staining showed a distinct co-localization with K7/K19. In chronic human liver disease, K23 expression increased in patients with a more prominent inflammation/fibrosis. A dramatic upregulation (>200times) was observed in patients with acute liver failure (ALF) and end-stage primary biliary cholangitis (PBC). Patients with alcoholic liver cirrhosis displayed increased K23 serum levels. In primary hepatocytes as well as hepatobiliary cell lines, treatment with TNF-related weak inducer of apoptosis (TWEAK), and the type I acute phase inducer interleukin (IL)-1β but not the type II inducer IL-6 elevated K23 expression.
  
  
  
  K23 represents a specific, stress-inducible DR marker, whose levels correlate with liver disease severity. K23 may represent a useful non-invasive DR marker.
  
  
  
  Ductular reaction represents a basic response to liver injury and correlates with liver disease severity. Our study identifies K23 as a novel ductular reaction marker in mice and humans.
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany.
authors.forename: Nurdan
authors.initials: N
authors.lastname: Guldiken
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany.
authors.forename: Gokce
authors.initials: G
authors.lastname: Kobazi Ensari
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Pooja
authors.initials: P
authors.lastname: Lahiri
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris F-75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, F-75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France; Université Paris Diderot, IUH, F-75010 Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany.
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France; Pathology Department, GH Paris-Seine-Saint-Denis, APHP, Bondy, France; Centre de ressources biologiques BB-0033-00027 - Hôpital Jean Verdier, GH Paris-Seine-Saint-Denis, APHP, Bondy, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.affiliation: Department of Nephrology and Institute of Pathology, RWTH University Hospital Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris F-75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, F-75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France; Université Paris Diderot, IUH, F-75010 Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, RWTH University Hospital Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany. Electronic address: pstrnad@ukaachen.de.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
mesh_terms: D000818:Animals; D006801:Humans; D007633:Keratins; D053530:Keratins, Type I; D008099:Liver; D008107:Liver Diseases; D051379:Mice; D011725:Pyridines
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C420247:KRT23 protein, human; D053530:Keratins, Type I; D011725:Pyridines; D007633:Keratins
keywords: Ductular reaction; Human liver diseases; Keratin 23; Liver progenitor cells