Spermidine Stimulates T Cell Protein-tyrosine Phosphatase-mediated Protection of Intestinal Epithelial Barrier Function

Penrose, Harrison M.; Marchelletta, Ronald R.; Krishnan, Moorthy; McCole, Declan F.

doi:10.1074/jbc.m113.475962

Cited by 26 publications

(44 citation statements)

References 39 publications

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“…3B,C). (21, 25) Administration of VSL#3 for 9 hrs following 24 hrs of IFN-γ treatment significantly reduced STAT-1 phosphorylation in a dose-dependent manner compared to IFN-γ-treated cells alone (p<0.05, n=3; Fig. 3B,C).…”

Section: Resultsmentioning

confidence: 90%

“…Previous studies employing the T 84 cell line used cycloheximide at a final concentration of 35.5 μM to inhibit protein synthesis. (25, 28) Therefore, T 84 cells grown as monolayers on permeable supports were treated with cycloheximide (35.5 μM) for 30 minutes followed by the addition of VSL#3 (10 6 CFU/mL) for 9 hours as this concentration and time point induced the greatest increase in TCPTP protein (c.f. Fig 1B).…”

Section: Resultsmentioning

confidence: 99%

“…(25, 30, 32, 33) To identify if the VSL#3-induced recovery of barrier function was associated with recovery of tight junction proteins, we performed immunofluorescence staining for the transmembrane protein occludin, the regulatory molecule ZO-1 and the cation-pore forming transmembrane protein claudin-2. IFN-γ treatment for 24 hrs was followed by 9 hrs treatment with VSL#3 as previously.…”

Section: Resultsmentioning

confidence: 99%

“…(21–23) Therefore, agents that increase the activity of TCPTP are of general interest as modifiers of inflammatory signaling events. (24, 25) The goal of this project was to determine the effects of different VSL#3 concentrations and incubation times on TCPTP expression and activity. Additionally, we sought to examine whether VSL#3 affects TCPTP regulation of IFN-γ signaling and can correct downstream effects on barrier integrity.…”

Section: Introductionmentioning

confidence: 99%

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VSL#3 Probiotic Stimulates T-cell Protein Tyrosine Phosphatase–mediated Recovery of IFN-γ–induced Intestinal Epithelial Barrier Defects

Krishnan

Penrose

Shah

et al. 2016

Inflammatory Bowel Diseases

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Background VSL#3 is a probiotic compound that has been used in the treatment of Inflammatory Bowel Disease (IBD). T-cell protein tyrosine phosphatase (TCPTP) is the protein product of the IBD candidate gene, PTPN2, and we have previously shown that it protects epithelial barrier function. The aim of this study was to investigate if VSL#3 improves intestinal epithelial barrier function against the effects of the IBD associated pro-inflammatory cytokine, interferon-gamma (IFN-γ) via activation of TCPTP. Methods Polarized monolayers of T84 intestinal epithelial cell (IEC) were treated with increasing concentrations of VSL#3 to determine effects on TCPTP expression and enzymatic activity. Therapeutic effects of VSL#3 against barrier disruption by IFN-γ were measured by transepithelial electrical resistance (TER) and FITC-dextran permeability. A novel TCPTP-deficient HT-29 IEC line was generated to study the role of TCPTP in mediating the effects of VSL#3. Tight junction protein distribution was assessed by confocal microscopy. Results VSL#3 increased TCPTP protein levels and enzymatic activity, correlating with a VSL#3-induced decrease in IFN-γ signaling. VSL#3 corrected the decrease in TER and the increase in epithelial permeability induced by IFN-γ. Moreover, the restorative effect of VSL#3 against IFN-γ signaling, epithelial permeability defects, altered expression and localization of the tight junction proteins claudin-2, occludin and ZO-1, were not realized in stable TCPTP/(PTPN2)-deficient HT-29 intestinal epithelial cells. Conclusion VSL#3 reduces IFN-γ signaling and IFN-γ-induced epithelial barrier defects in a TCPTP-dependent manner. These data point to a key role for TCPTP as a therapeutic target for restoration of barrier function by probiotics.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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VSL#3 Probiotic Stimulates T-cell Protein Tyrosine Phosphatase–mediated Recovery of IFN-γ–induced Intestinal Epithelial Barrier Defects

Krishnan

Penrose

Shah

et al. 2016

Inflammatory Bowel Diseases

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“…Published data indicate that activation of STAT3 inhibits occludin expression in epithelial cells [19]. Since PRL increases STAT3 phosphorylation in T84 cells, we infer that PRL modulates the occludin expression in T84 cells via modulating STAT3 activation.…”

Section: Prl Modulates Tight Junction Protein Occludin Expression In mentioning

confidence: 81%

Psychological Stress-Derived Prolactin Modulates Occludin Expression in Vaginal Epithelial Cells to Compromise Barrier Function

Liu

Song

2015

Cell Physiol Biochem

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This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Key Words Epithelial barrier • Psychological stress • Prolactin • Biological transport • T84 cellsAbstract Background/Aims: The causative factors of the vaginitis are not fully understood yet. Epithelial barrier dysfunction plays a critical role in the pathogenesis of vaginitis. This study aims to investigate the role of prolactin (PRL) in the causing the vaginal epithelial barrier dysfunction. Methods: Adult rats were treated with water-avoid-stress. The serum levels of PRL were determined by ELISA. T84 cell (T84 cells; a vaginal epithelial cell line) monolayers were prepared to be used assessing the epithelial barrier functions. The expression of occludin in T84 cells was assessed by Chromatin immunoprecipitation assay, methylation specific PCR, real time quantitative RT-PCR and Western blotting. Results: The results showed that psychological stress markedly increased the serum levels of PRL in the rat vaginal epithelia. Exposure of T84 cells to PRL in the culture markedly increased the phosphorylation of STAT3 and suppressed the expression of occludin in the cells; the transepithelial electric resistance was decreased and the permeability to a macromolecular tracer was increased in the T84 monolayers, which was mimicked by blocking STAT3, or abolished by over expression of occludin in the epithelial cells. Conclusions: Psychological stress-derived PRL induces vaginal epithelial barrier dysfunction by inhibiting the expression of occludin.

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Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction

et al. 2014

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Congenital tufting enteropathy (CTE) is a devastating diarrheal disease seen in infancy that is typically associated with villous changes and the appearance of epithelial tufts. We previously found mutations in epithelial cell adhesion molecule (EpCAM) to be causative in CTE. We developed a knock-down cell model of CTE through transfection of an EpCAM shRNA construct into T84 colonic epithelial cells to elucidate the in vitro role of EpCAM in barrier function and ion transport. Cells with EpCAM deficiency exhibited decreased electrical resistance, increased permeability, and decreased ion transport. Based on mutations in CTE patients, an in vivo mouse model was developed, with tamoxifen-inducible deletion of exon 4 in Epcam resulting in mutant protein with decreased expression. Tamoxifen treatment of EpcamΔ4/Δ4 mice resulted in pathological features of villous atrophy and epithelial tufts, similar to those in human CTE patients, within 4 days post induction. EpcamΔ4/Δ4 mice also showed decreased expression of tight junctional proteins, increased permeability, and decreased ion transport in the intestines. Taken together, these findings reveal mechanisms that may underlie disease in CTE.Key messagesKnock-down EpCAM cell model of congenital tufting enteropathy was developed.In vivo inducible mouse model was developed resulting in mutant EpCAM protein.Cells with EpCAM deficiency demonstrated barrier and ion transport dysfunction.Tamoxifen-treated EpcamΔ4/Δ4 mice demonstrated pathological features.EpcamΔ4/Δ4 mice showed improper barrier function and ion transport.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1239-x) contains supplementary material, which is available to authorized users.

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Spermidine Stimulates T Cell Protein-tyrosine Phosphatase-mediated Protection of Intestinal Epithelial Barrier Function

Cited by 26 publications

References 39 publications

VSL#3 Probiotic Stimulates T-cell Protein Tyrosine Phosphatase–mediated Recovery of IFN-γ–induced Intestinal Epithelial Barrier Defects

VSL#3 Probiotic Stimulates T-cell Protein Tyrosine Phosphatase–mediated Recovery of IFN-γ–induced Intestinal Epithelial Barrier Defects

Psychological Stress-Derived Prolactin Modulates Occludin Expression in Vaginal Epithelial Cells to Compromise Barrier Function

Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction

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