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

Gastroenterology. 2013 May;144(5):1116-28. doi: 10.1053/j.gastro.2013.01.055. Epub 2013 Feb 4.


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.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Anti-Idiotypic / immunology
  • Antibodies, Anti-Idiotypic / metabolism
  • Bile / metabolism*
  • Blotting, Western
  • Cell Membrane Permeability / immunology*
  • Cells, Cultured
  • Cholangitis / immunology*
  • Cholangitis / metabolism
  • Cholangitis / pathology
  • Cytokines / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Humans
  • Immunity, Cellular
  • Immunoglobulin G / immunology*
  • Male
  • Middle Aged
  • Th2 Cells / metabolism*
  • Tight Junctions


  • Antibodies, Anti-Idiotypic
  • Cytokines
  • Immunoglobulin G