title: Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.
abstract: OBJECTIVE
  Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved.
  
  
  METHODS
  We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC.
  
  
  RESULTS
  We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice.
  
  
  CONCLUSIONS
  Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Mair
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Doris
authors.initials: D
authors.lastname: Schneller
authors.forename: Monica
authors.initials: M
authors.lastname: Musteanu
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Judith
authors.initials: J
authors.lastname: Gumhold
authors.forename: Christian
authors.initials: C
authors.lastname: Schuster
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tauber
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.forename: Leander
authors.initials: L
authors.lastname: Blaas
authors.forename: Jan Wilhelm
authors.initials: JW
authors.lastname: Kornfeld
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000818:Animals; D001647:Bile Acids and Salts / Q000633:toxicity; D049109:Cell Proliferation; D015209:Cholangitis, Sclerosing / Q000150:complications*; D019610:Cytoprotection; D008099:Liver / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008115:Liver Regeneration; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C494087:Stat3 protein, mouse