Transforming Growth Factor-β Regulation of Epithelial Tight Junction Proteins Enhances Barrier Function and Blocks Enterohemorrhagic Escherichia coli O157:H7-Induced Increased Permeability

The enteric microbiota contributes to the pathogenesis of inflammatory bowel disease, but the pathways involved and bacterial participants may vary in different hosts. We previously reported that some components of the human commensal microbiota, particularly Clostridium perfringens ( C. perfringens), have the proteolytic capacity for host matrix degradation and reduce transepithelial resistance. Here, we examined the C. perfringens-derived proteolytic activity against epithelial tight junction proteins using human intestinal epithelial cell lines. We showed that the protein levels of E-cadherin, occludin, and junctional adhesion molecule 1 decrease in colonic cells treated with C. perfringens culture supernatant. E-cadherin ectodomain shedding in C. perfringens-stimulated intestinal epithelial cells was detected with antibodies against the extracellular domain of E-cadherin, and we demonstrate that this process occurs in a time- and dose-dependent manner. In addition, we showed that the filtered sterile culture supernatant of C. perfringens has no cytotoxic activity on the human intestinal cells at the concentrations used in this study. The direct cleavage of E-cadherin by the proteases from the C. perfringens culture supernatant was confirmed by C. perfringens supernatant-induced in vitro degradation of the human recombinant E-cadherin. We conclude that C. perfringens culture supernatant mediates digestion of epithelial cell junctional proteins, which is likely to enable access to the extracellular matrix components by the paracellular pathway.

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MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA

Molecular and Cellular Biology ◽

10.1128/mcb.00941-08 ◽

2008 ◽

Vol 28 (22) ◽

pp. 6773-6784 ◽

Cited By ~ 458

Author(s):

William Kong ◽

Hua Yang ◽

Lili He ◽

Jian-jun Zhao ◽

Domenico Coppola ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Growth Factor ◽

Tight Junction ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Migration And Invasion ◽

Advanced Malignancy ◽

Mesenchymal Transition ◽

Cell Migration And Invasion

ABSTRACT Transforming growth factor β (TGF-β) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-β-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-β-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-β induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3′ untranslated region largely reversed the phenotype induced by miR-155 and TGF-β. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-β-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.

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Vascular Endothelial Growth Factor Induces Rapid Phosphorylation of Tight Junction Proteins Occludin and Zonula Occluden 1

Journal of Biological Chemistry ◽

10.1074/jbc.274.33.23463 ◽

1999 ◽

Vol 274 (33) ◽

pp. 23463-23467 ◽

Cited By ~ 388

Author(s):

David A. Antonetti ◽

Alistair J. Barber ◽

Leigh Ann Hollinger ◽

Ellen B. Wolpert ◽

Thomas W. Gardner

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Tight Junction ◽

Vascular Endothelial ◽

Tight Junction Proteins ◽

Endothelial Growth Factor ◽

Junction Proteins

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Intestinal epithelial barrier function and tight junction proteins with heat and exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.00536.2015 ◽

2016 ◽

Vol 120 (6) ◽

pp. 692-701 ◽

Cited By ~ 88

Author(s):

Karol Dokladny ◽

Micah N. Zuhl ◽

Pope L. Moseley

Keyword(s):

Heat Stress ◽

Tight Junction ◽

Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Tight Junction Proteins ◽

Intestinal Epithelial Barrier ◽

Epithelial Tight Junction ◽

Junction Proteins

A single layer of enterocytes and tight junctions (intercellular multiprotein complexes) form the intestinal epithelial barrier that controls transport of molecules through transcellular and paracellular pathways. A dysfunctional or “leaky” intestinal tight junction barrier allows augmented permeation of luminal antigens, endotoxins, and bacteria into the blood stream. Various substances and conditions have been shown to affect the maintenance of the intestinal epithelial tight junction barrier. The primary focus of the present review is to analyze the effects of exertional or nonexertional (passive hyperthermia) heat stress on tight junction barrier function in in vitro and in vivo (animals and humans) models. Our secondary focus is to review changes in tight junction proteins in response to exercise or hyperthermic conditions. Finally, we discuss some pharmacological or nutritional interventions that may affect the cellular mechanisms involved in maintaining homeostasis of the intestinal epithelial tight junction barrier during heat stress or exercise.

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Tricellular Tight Junction Protein Tricellulin Is Targeted by the Enteropathogenic Escherichia coli Effector EspG1, Leading to Epithelial Barrier Disruption

Infection and Immunity ◽

10.1128/iai.00700-16 ◽

2016 ◽

Vol 85 (1) ◽

Cited By ~ 6

Author(s):

Vijay Morampudi ◽

Franziska A. Graef ◽

Martin Stahl ◽

Udit Dalwadi ◽

Victoria S. Conlin ◽

...

Keyword(s):

Escherichia Coli ◽

Tight Junction ◽

Significant Loss ◽

Effector Proteins ◽

Epithelial Barrier ◽

Tight Junction Proteins ◽

Barrier Dysfunction ◽

Barrier Disruption ◽

Junction Protein ◽

Junction Proteins

ABSTRACT Enteropathogenic Escherichia coli (EPEC)-induced diarrhea is often associated with disruption of intestinal epithelial tight junctions. Although studies have shown alterations in the expression and localization of bicellular tight junction proteins during EPEC infections, little is known about whether tricellular tight junction proteins (tTJs) are affected. Using Caco-2 cell monolayers, we investigated if EPEC is capable of targeting the tTJ protein tricellulin. Our results demonstrated that at 4 h postinfection, EPEC induced a significant reduction in tricellulin levels, accompanied by a significant loss of transepithelial resistance (TEER) and a corresponding increase in paracellular permeability. Conversely, cells overexpressing tricellulin were highly resistant to EPEC-induced barrier disruption. Confocal microscopy revealed the distribution of tricellulin into the plasma membrane of infected epithelial cells and confirmed the localization of EPEC aggregates in close proximity to tTJs. Moreover, infections with EPEC strains lacking genes encoding specific type III secreted effector proteins demonstrated a crucial role for the effector EspG1 in modulating tricellulin expression. Complementation studies suggest that the EspG-induced depletion of tricellulin is microtubule dependent. Overall, our results show that EPEC-induced epithelial barrier dysfunction is mediated in part by EspG1-induced microtubule-dependent depletion of tricellulin.

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Transforming growth factor-β1 decreases epithelial tight junction integrity in chronic rhinosinusitis with nasal polyps

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2017.08.045 ◽

2018 ◽

Vol 141 (3) ◽

pp. 1160-1163.e9 ◽

Cited By ~ 13

Author(s):

Jian Jiao ◽

Ming Wang ◽

Su Duan ◽

Yifan Meng ◽

Na Meng ◽

...

Keyword(s):

Growth Factor ◽

Tight Junction ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Epithelial Tight Junction

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Route of intestinal absorption and tissue distribution of iron contained in the novel phosphate binder ferric citrate

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa053 ◽

2020 ◽

Vol 35 (7) ◽

pp. 1136-1144

Author(s):

Nosratola D Vaziri ◽

Ane C F Nunes ◽

Hyder Said ◽

Mahyar Khazaeli ◽

Han Liu ◽

...

Keyword(s):

Fatty Acid ◽

Tight Junction ◽

Iron Content ◽

Phosphate Binder ◽

Serum Iron ◽

Iron Absorption ◽

Distal Colon ◽

Tight Junction Proteins ◽

Epithelial Tight Junction ◽

Junction Proteins

Abstract Background Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here. Methods Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions. Results CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon’s epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration. Conclusion Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

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