Epithelial barrier dysfunction in lymphocytic colitis through cytokine-dependent internalization of claudin-5 and-8

被引:28
作者
Barmeyer, Christian [1 ,2 ]
Erko, Irene [1 ]
Awad, Karem [2 ]
Fromm, Anja [2 ]
Bojarski, Christian [1 ]
Meissner, Svenja [1 ]
Loddenkemper, Christoph [3 ,6 ]
Kerick, Martin [4 ]
Siegmund, Britta [1 ]
Fromm, Michael [2 ]
Schweiger, Michal R. [4 ,5 ]
Schulzke, Joerg-Dieter [1 ,2 ]
机构
[1] Charite, Dept Gastroenterol Infect Dis & Rheumatol, Campus Benjamin Franklin, Berlin, Germany
[2] Charite, Inst Clin Physiol, Campus Benjamin Franklin,Hindenburgdamm 30, D-12203 Berlin, Germany
[3] Charite, Inst Pathol, Campus Benjamin Franklin, Berlin, Germany
[4] Max Planck Inst Mol Genet, Berlin, Germany
[5] Univ Cologne, Cologne Ctr Genom, Cologne, Germany
[6] Inst Pathol PathoTres, Berlin, Germany
关键词
Lymphocytic colitis; Tight junction; Claudin; Cytokines; INFLAMMATORY-BOWEL-DISEASE; TIGHT JUNCTION STRUCTURE; MICROSCOPIC COLITIS; COLLAGENOUS COLITIS; ULCERATIVE-COLITIS; CROHNS-DISEASE; HT-29/B6; CELLS; NA+ ABSORPTION; ION-TRANSPORT; IN-VIVO;
D O I
10.1007/s00535-017-1309-2
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:1090 / 1100
页数:11
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