TY - JOUR
T1 - Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier
AU - Müller, Tobias
AU - Beutler, Claudia
AU - Picó, Almudena Hurtado
AU - Otten, Morgane
AU - Dürr, Angelika
AU - Al-Abadi, Hussain
AU - Guckelberger, Olaf
AU - Meyer Zum Büschenfelde, Dirk
AU - Jöhrens, Korinna
AU - Volkmann, Martin
AU - Lankisch, Tim
AU - Voigtländer, Torsten
AU - Anders, Mario
AU - Shibolet, Oren
AU - Jefferson, Douglas M.
AU - Podolsky, Daniel K.
AU - Fischer, Andreas
AU - Veltzke-Schlieker, Wilfried
AU - Adler, Andreas
AU - Baumgart, Daniel C.
AU - Sturm, Andreas
AU - Wiedenmann, Bertram
AU - Schott, Eckart
AU - Berg, Thomas
N1 - Funding Information:
Funding This work was supported by the Deutsche Forschungsgemeinschaft , grant MU 2864/1-1 (to TM).
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
KW - Cholangiocyte
KW - Cholangiopathy
KW - Chronic Biliary Inflammation
KW - Paracellular Pore and Leak Pathway
UR - https://www.scopus.com/pages/publications/84876500520
U2 - 10.1053/j.gastro.2013.01.055
DO - 10.1053/j.gastro.2013.01.055
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AN - SCOPUS:84876500520
SN - 0016-5085
VL - 144
SP - 1116
EP - 1128
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -