Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier

Tobias Müller, Claudia Beutler, Almudena Hurtado Picó, Morgane Otten, Angelika Dürr, Hussain Al-Abadi, Olaf Guckelberger, Dirk Meyer Zum Büschenfelde, Korinna Jöhrens, Martin Volkmann, Tim Lankisch, Torsten Voigtländer, Mario Anders, Oren Shibolet, Douglas M. Jefferson, Daniel K. Podolsky, Andreas Fischer, Wilfried Veltzke-Schlieker, Andreas Adler, Daniel C. BaumgartAndreas Sturm, Bertram Wiedenmann, Eckart Schott, Thomas Berg

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27 Scopus citations

Abstract

Background & Aims: 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.

Original languageEnglish (US)
Pages (from-to)1116-1128
Number of pages13
JournalGastroenterology
Volume144
Issue number5
DOIs
StatePublished - May 2013

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Keywords

  • Cholangiocyte
  • Cholangiopathy
  • Chronic Biliary Inflammation
  • Paracellular Pore and Leak Pathway

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Müller, T., Beutler, C., Picó, A. H., Otten, M., Dürr, A., Al-Abadi, H., Guckelberger, O., Meyer Zum Büschenfelde, D., Jöhrens, K., Volkmann, M., Lankisch, T., Voigtländer, T., Anders, M., Shibolet, O., Jefferson, D. M., Podolsky, D. K., Fischer, A., Veltzke-Schlieker, W., Adler, A., ... Berg, T. (2013). Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier. Gastroenterology, 144(5), 1116-1128. https://doi.org/10.1053/j.gastro.2013.01.055