title: Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier.
abstract: OBJECTIVE
  IgG4-related cholangitis is a chronic inflammatory biliary disease that involves different parts of the pancreatobiliary system, but little is known about its mechanisms of pathogenesis. A T-helper (Th) 2 cell cytokine profile predominates in liver tissues from these patients. We investigated whether Th2 cytokines disrupt the barrier function of biliary epithelial cells (BECs) in patients with IgG4-related cholangitis.
  
  
  METHODS
  We assessed the Th2 cytokine profile in bile samples and brush cytology samples from 16 patients with IgG4-related cholangitis and respective controls, and evaluated transcription of tight junction (TJ)-associated proteins in primary BECs from these patients. The effect of Th2 cytokines on TJ-mediated BEC barrier function and wound closure was examined by immunoblot, transepithelial resistance, charge-selective Na(+)/Cl(-) permeability, and 4-kDa dextran flux analyses.
  
  
  RESULTS
  Bile samples from patients with IgG4-related cholangitis had significant increases in levels of Th2 cytokines, interleukin (IL)-4, and IL-5. IL-13 was not detected in bile samples, but polymerase chain reaction analysis of whole-brush cytology samples from patients with IgG4-related cholangitis revealed increased levels of IL-13 mRNA, compared with controls. BECs isolated from the brush cytology samples revealed decreased levels of claudin-1 and increased levels of claudin-2 mRNAs. In vitro, IL-4 and IL-13 significantly reduced TJ-associated BEC barrier function by activating claudin-2-mediated paracellular pore pathways. Th2 cytokines also impaired wound closure in BEC monolayers.
  
  
  CONCLUSIONS
  Th2 cytokines predominate in bile samples from patients with IgG4-related cholangitis and disrupt the TJ-mediated BEC barrier in vitro. Subsequent increases in biliary leaks might contribute to the pathogenesis of chronic biliary inflammation in these patients.
authors: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. tobias.mueller@medizin.uni-leipzig.de
authors: Tobias
authors: T
authors: Müller
authors: Claudia
authors: C
authors: Beutler
authors: Almudena Hurtado
authors: AH
authors: Picó
authors: Morgane
authors: M
authors: Otten
authors: Angelika
authors: A
authors: Dürr
authors: Hussain
authors: H
authors: Al-Abadi
authors: Olaf
authors: O
authors: Guckelberger
authors: Dirk
authors: D
authors: Meyer Zum Büschenfelde
authors: Korinna
authors: K
authors: Jöhrens
authors: Martin
authors: M
authors: Volkmann
authors: Tim
authors: T
authors: Lankisch
authors: Torsten
authors: T
authors: Voigtländer
authors: Mario
authors: M
authors: Anders
authors: Oren
authors: O
authors: Shibolet
authors: Douglas M
authors: DM
authors: Jefferson
authors: Daniel K
authors: DK
authors: Podolsky
authors: Andreas
authors: A
authors: Fischer
authors: Wilfried
authors: W
authors: Veltzke-Schlieker
authors: Andreas
authors: A
authors: Adler
authors: Daniel C
authors: DC
authors: Baumgart
authors: Andreas
authors: A
authors: Sturm
authors: Bertram
authors: B
authors: Wiedenmann
authors: Eckart
authors: E
authors: Schott
authors: Thomas
authors: T
authors: Berg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D015153:Blotting, Western; D002463:Cell Membrane Permeability / Q000276:immunology*; D002478:Cells, Cultured; D002761:Cholangitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018418:Th2 Cells / Q000378:metabolism*; D019108:Tight Junctions
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016207:Cytokines; D007074:Immunoglobulin G