Universität zu Köln

Barmeyer, Christian, Erko, Irene, Awad, Karem, Fromm, Anja ORCID: 0000-0003-4091-9612, Bojarski, Christian, Meissner, Svenja, Loddenkemper, Christoph, Kerick, Martin ORCID: 0000-0002-6298-4514, Siegmund, Britta ORCID: 0000-0002-0055-958X, Fromm, Michael ORCID: 0000-0003-4497-7983, Schweiger, Michal R. and Schulzke, Joerg-Dieter (2017). Epithelial barrier dysfunction in lymphocytic colitis through cytokine-dependent internalization of claudin-5 and-8. J. Gastroenterol., 52 (10). S. 1090 - 1101. TOKYO: SPRINGER JAPAN KK. ISSN 1435-5922

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Abstract

Background Watery diarrhea is the cardinal symptom of lymphocytic colitis (LC). We have previously shown that colonic Na malabsorption is one of the major pathologic alterations of LC and found evidence for an epithelial barrier defect. On these grounds, this study aimed to identify the inherent mechanisms of this epithelial barrier dysfunction and its regulatory features. Methods Epithelial resistance (R-epi) was determined by one-path impedance spectroscopy and H-3-mannitol fluxes were performed on biopsies from sigmoid colon in miniaturized Ussing chambers. Tight junction proteins were analyzed by Western blot and confocal microscopy. Inflammatory signaling was characterized in HT-29/B6 cells. Apoptosis and mucosal surface parameters were quantified morphologically. Results Repi was reduced to 53% and H-3-mannitol fluxes increased 1.7-fold in LC due to lower expression of claudin-4, -5, and -8 and altered subcellular claudin-5 and -8 distributions off the tight junction. TNF alpha and IFN gamma could mimic subcellular redistribution in HT-29/B6 cells, a process which was independent on MLCK activation. Epithelial apoptosis did not contribute to barrier dysfunction in LC and mucosal surface area was unchanged. Conclusions Epithelial barrier dysfunction in LC occurs through downregulation of claudin-4, -5, and -8, and redistribution of claudin-5 and -8 off the tight junction, which contributes to diarrhea by a leak-flux mechanism. The key effector cytokines TNF alpha and IFNc gamma turned out to be the trigger for redistribution of claudin-5 and -8. Thus, alongside sodium malabsorption, leak-flux is yet another important diarrheal mechanism in LC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Barmeyer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Erko, Irene UNSPECIFIED UNSPECIFIED UNSPECIFIED Awad, Karem UNSPECIFIED UNSPECIFIED UNSPECIFIED Fromm, Anja UNSPECIFIED orcid.org/0000-0003-4091-9612 UNSPECIFIED Bojarski, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Meissner, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Loddenkemper, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Siegmund, Britta UNSPECIFIED orcid.org/0000-0002-0055-958X UNSPECIFIED Fromm, Michael UNSPECIFIED orcid.org/0000-0003-4497-7983 UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulzke, Joerg-Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-216238
DOI:	10.1007/s00535-017-1309-2
Journal or Publication Title:	J. Gastroenterol.
Volume:	52
Number:	10
Page Range:	S. 1090 - 1101
Date:	2017
Publisher:	SPRINGER JAPAN KK
Place of Publication:	TOKYO
ISSN:	1435-5922
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INFLAMMATORY-BOWEL-DISEASE; TIGHT JUNCTION STRUCTURE; MICROSCOPIC COLITIS; COLLAGENOUS COLITIS; ULCERATIVE-COLITIS; CROHNS-DISEASE; HT-29/B6 CELLS; NA+ ABSORPTION; ION-TRANSPORT; IN-VIVO Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21623