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PGE2 promotes Ca2+-mediated epithelial barrier disruption through EP1 and EP4 receptors in Caco-2 cell monolayers

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We recently demonstrated that PGE(2) induces the disruption of the intestinal epithelial barrier function. In the present study, our objectives were to study the role of PGE(2) receptors (EP(1)-EP(4)) and the signaling pathways involved in this event. Paracellular permeability (PP) was assessed in differentiated Caco-2 cell cultures from d-mannitol fluxes and transepithelial electrical resistance (TER) in the presence of different PGE(2) receptor agonists (carbacyclin, sulprostone, butaprost, ONO-AE1-259, ONO-AE-248, GR63799, and ONO-AE1-329) and antagonists (ONO-8711, SC-19220, AH-6809, ONO-AE3-240, ONO-AE3-208, and AH-23848). The results indicate that EP(1) and EP(4) but not EP(2) and EP(3) might be involved in PP regulation. These effects were mediated through PLC-inositol trisphosphate (IP(3))-Ca(2+) and cAMP-PKA signaling pathways, respectively. We also observed an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) strengthened by cAMP formation indicating a cross talk interaction of these two pathways. Moreover, the participation of a conventional PKC isoform was shown. The results also indicate that the increase in PP may be correlated with the redistribution of occludin, zona occludens 1 (ZO-1), and the perijunctional actin ring together with an increase in myosin light chain kinase activity. Although the disruption of epithelial barrier function observed in inflammatory bowel disease (IBD) patients has been traditionally attributed to cytokines, the present study focused on the role of PGE(2) in PP regulation, as mucosal levels of this eicosanoid are also increased in these inflammatory processes.

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Versió postprint del document publicat a:

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American Journal of Physiology-Cell Physiology, 2010, vol. 299, p. 324-334

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(c) American Physiological Society, 2010

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Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)

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PGE2 promotes Ca2+-mediated epithelial barrier disruption through EP1 and EP4 receptors in Caco-2 cell monolayers