Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis

Schmitz, H.; Barmeyer, Christian; Fromm, Michael; Runkel, N.; Foss, Hans‐Dieter; Bentzel, Carl J.; Riecken, Ernst–Otto; Schulzke, Jörg–Dieter

doi:10.1016/s0016-5085(99)70126-5

Cited by 531 publications

(407 citation statements)

References 32 publications

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“…An accumulation of polymorphic mononuclear cells at sites of inflammation, changes in cytokine levels (Andus et al, 1991;McCormack et al, 2001;Nikolaus et al, 1998) and increased rates of epithelial apoptosis (Anderson, 2000;Iwamoto et al, 1996;Levine, 2000;Sträter et al, 1997) were found to be associated with an increased permeability of the intestinal barrier. In human HT-29/B6 cells, increased cytokine levels resulted in a decrease in the transepithelial resistance and altered tight junction strand formation (Schmitz et al, 1999a). This, at least in part, appears to be regulated by the repression of the occludin promoter in response to TNF-α and IFN-γ (Mankertz et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The specific fates of tight junction proteins in apoptotic epithelial cells

Bojarski

Weiske

Schöneberg³

et al. 2004

Journal of Cell Science

153

129

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The polarized morphology of epithelial cells depends on the establishment and maintenance of characteristic intercellular junctions. The dramatic morphological changes observed in apoptotic epithelial cells were ascribed at least in part to the specific fragmentation of components of adherens junctions and desmosomes. Little, however, is known about tight junctions during apoptosis. We have found that after induction of apoptosis in epithelial cells, tight junction proteins undergo proteolytic cleavage in a distinctive manner correlated with a disruption of tight junctions. The transmembrane protein occludin and, likewise, the cytoplasmic adaptor proteins ZO-1 and ZO-2 are fragmented by caspase cleavage. In addition, occludin is cleaved at an extracellular site by a metalloproteinase. The caspase cleavage site in occludin was mapped C-terminally to Asp320 within the C-terminal cytoplasmic domain. Mutagenesis of this site efficiently blocked fragmentation. In the presence of caspase and/or metalloproteinase inhibitors, fragmentation of occludin, ZO-1 and ZO-2 was blocked and cellular morphology was almost fully preserved. Interestingly, two members of the claudin family of transmembrane tight junction proteins exhibited a different behavior. While the amount of claudin-2 protein was reduced similarly to occludin, ZO-1 and ZO-2, claudin-1 was either fully preserved or was even increased in apoptotic cells.

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Section: Discussionmentioning

confidence: 99%

The specific fates of tight junction proteins in apoptotic epithelial cells

Bojarski

Weiske

Schöneberg³

et al. 2004

Journal of Cell Science

153

129

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“…However, the barrier becomes impaired during inflammatory bowel disease (IBD). As a result, a large quantity of endotoxin can enter into systemic circulation through the impaired intestinal mucosa [1,2] . In addition, oxygen free radicals (OFRs) and proinflammatory cytokines are induced, facilitating impairment of intestinal mucosal permeability [3][4][5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

Balsalazine decreases intestinal mucosal permeability of dextran sulfate sodium-induced colitis in mice

Liu

Qiao

et al. 2009

Acta Pharmacol Sin

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Aim:To investigate the effect of balsalazine treatment on intestinal mucosal permeability in dextran sulfate sodium (DSS)-induced colitis and to determine the mechanism of the balsalazine-induced changes. Methods: Experimental colitis was induced in C57BL/6J mice by the administration of 5% DSS. Balsalazine was administered intragastrically at doses of 42, 141, and 423 mg/kg. The disease activity index (DAI) score was evaluated and colon tissue was collected for the assessment of histological changes. The amount of malondialdehyde (MDA) in the colon was determined, along with the activity of myeloperoxidase (MPO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Mucosa from the small intestine was collected to determine the levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The mucosa was ultrastructurally examined with transmission electron microscopy and intestinal permeability was assayed using Evans blue. Results: Balsalazine was found to reduce the DAI score and the histological index (HI) score, decrease the MDA content and the activity of MPO, and increase the activity of SOD and GSH-Px in colitis mice. At the same time, balsalazine ameliorated microvillus and tight junction structure, resulting in a decrease in the amount of Evans blue permeating into the intestinal wall and the levels of TNF-α and IFN-γ in colitis mice. Conclusion: In colitis mice, the anti-colitis effect of balsalazine results in a decrease in intestinal mucosal permeability. The mechanism of this effect is partly associated with balsalazine's antioxidative and anti-inflammatory effects.

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“…[22][23][24] Interestingly, IBD is associated with reduced strand numbers and an increase in strand breakages and these changes are associated with a marked decrease in electrical resistance across the epithelium. 25 Junctional proteins show reduced expression or changes in distribution in gut inflammation. [26][27][28] The dynamic nature of tight junctions is well demonstrated by the ability of cytokines and growth factors to modulate tight junction protein expression, regulate junction assembly and change epithelial permeability.…”

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confidence: 99%

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

Prasad

Mingrino

Kaukinen

et al. 2005

Laboratory Investigation

419

384

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Claudin proteins comprise a recently described family of tight junction proteins that differentially regulate paracellular permeability. Since other tight junction proteins show alterations in distribution or expression in inflammatory bowel disease (IBD) we assessed expression of claudins (CL) 2, 3 and 4 in IBD. CL 2 was strongly expressed along the inflamed crypt epithelium, whilst absent or barely detectable in normal colon. In contrast, CL 3 and 4 were present throughout normal colonic epithelium and were reduced or redistributed in the diseased surface epithelium. In a T84-cell culture model of the gut barrier, paracellular permeability decreased with time after plating and correlated with a marked decrease in the expression of CL 2. Addition of IFNc/TNFa led to further decreases in CL 2 and 3, the redistrbution of CL 4 and a marked increase in paracellular permeability. Conversely, IL-13 dramatically increased CL 2, with little effect on CL 3 or 4, but also resulted in increased paracellular permeability. Expression of CL 2 did not correlate with proliferation or junctional reorganisation after calcium ion depletion. Re-expression of CL 2 in response to IL-13 was inhibited by phophatidylinositol 3 kinase inhibitor, LY294002, which also restored the ion permeability to previous levels. CL 2 expression could be stimulated in the absence of IL-13 by activation of phospho-Akt in the phophatidylinositol 3 kinase pathway. These results suggest that INFc/TNFa and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.

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Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis

Cited by 531 publications

References 32 publications

The specific fates of tight junction proteins in apoptotic epithelial cells

The specific fates of tight junction proteins in apoptotic epithelial cells

Balsalazine decreases intestinal mucosal permeability of dextran sulfate sodium-induced colitis in mice

Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells

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