title: (-)-Epicatechin in the prevention of tumor necrosis alpha-induced loss of Caco-2 cell barrier integrity.
abstract: An increased permeability of the intestinal barrier is proposed as a major event in the pathophysiology of inflammatory bowel diseases (IBD). Tumor necrosis alpha (TNFα) plays a central role in IBD pathogenesis, in part promoting tight function (TJ) barrier dysfunction. Food extracts enriched in (-)-epicatechin (EC) prevent the development or improve the progression of IBD in animal models. This study investigated the capacity of EC to inhibit TNFα-induced permeabilization of Caco-2 cell monolayers, characterizing the underlying mechanisms. Caco-2 cells differentiated into intestinal epithelial cells were incubated in the absence/presence of TNFα, with or without the addition of 0.5-5 μM EC. TNFα triggered cell monolayer permeabilization, decreasing transepithelial electrical resistance (TEER) and increasing the paracellular transport of fluorescein sulfonic acid. The permeabilizing effects of TNFα were not due to Caco-2 cell apoptosis as evaluated by DNA fragmentation, caspase 3 and 9 activation, and cell morphology. EC prevented TNFα-triggered Caco-2 monolayer permeabilization and acted inhibiting the associated: (i) NADPH oxidase (NOX)-mediated increased oxidant production, (ii) NF-κB (IκBα phosphorylation, p50 and RelA nuclear transport, and nuclear NF-κB-DNA binding) and ERK1/2 activation, (iii) increased myosin light kinase expression, and decreased TJ protein ZO-1 levels. In summary, EC prevented TNFα-mediated Caco-2 cell barrier permeabilization in part through the inhibition of NOX/NF-κB activation and downstream TJ disruption. Diets rich in EC could contribute to ameliorate IBD-associated increased intestinal permeability.
authors: Department of Nutrition, University of California, Davis, CA, USA; Department of Environmental Toxicology, University of California, Davis, CA, USA.
authors: Telma C
authors: TC
authors: Contreras
authors: Department of Nutrition, University of California, Davis, CA, USA; Department of Environmental Toxicology, University of California, Davis, CA, USA.
authors: Elisabetta
authors: E
authors: Ricciardi
authors: Department of Nutrition, University of California, Davis, CA, USA; Department of Environmental Toxicology, University of California, Davis, CA, USA.
authors: Eleonora
authors: E
authors: Cremonini
authors: Department of Nutrition, University of California, Davis, CA, USA; Department of Environmental Toxicology, University of California, Davis, CA, USA. Electronic address: poteiza@ucdavis.edu.
authors: Patricia I
authors: PI
authors: Oteiza
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport; D018938:Caco-2 Cells; D002392:Catechin / Q000494:pharmacology*; D002454:Cell Differentiation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000166:cytology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D019108:Tight Junctions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D005452:Fluoresceins; D016328:NF-kappa B; D016877:Oxidants; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C094528:fluorescein sulfonic acid; D002392:Catechin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: (−)-Epicatechin; Inflammation; Intestinal barrier; Intestinal permeability; NADPH oxidase; Tight junction