Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa

Erica F Diezmos; Irit Markus; D S Perera; Steven Gan; Li Zhang; Shaun L Sandow; Paul P Bertrand; Lu Liu

doi:10.3389/fphar.2018.00865

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Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa

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Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa

Erica F Diezmos, Irit Markus, D S Perera, Steven Gan, Li Zhang, Shaun L Sandow, Paul P Bertrand and Lu Liu

Frontiers in Pharmacology, Vol.9, 865

2018

DOI: https://doi.org/10.3389/fphar.2018.00865

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Abstract

pannexin-1

P2X7 receptor

colonic inflammation

human colitis

tissue explants

Introduction: The pannexin-1 (Panx1) channels are found in many cell types, and ATP released from these channels can act on nearby cells activating purinergic P2X7 receptors (P2X7R) which lead to inflammation. Although Panx1 and P2X7R are implicated in the process of inflammation and cell death, few studies have looked at the role they play in inflammatory bowel disease in human. Hence, the aim of the present study was to investigate the function of Panx1 and P2X7R in an ex vivo colitis model developed from human colonic mucosal explants. Materials and Methods: Healthy human colonic mucosal strips (4 x 10 mm) were incubated in carbogenated culture medium at 37 degrees C for 16 h. Proinflammatory cytokines TNF alpha and IL-1 beta (each 10 ng/mL) were used to induce colitis in mucosal strips, and the effects of Panx1 and P2X7R on cytokines-induced tissue damage were determined in the presence of the Panx1 channel blocker (10)Panx1 (100 mu M) and P2X7R antagonist A438079 (100 mu M). The effects of (10)Panx1 and A438079 on cytokines-enhanced epithelial permeability were also studied using Caco-2 cells. Results: Histological staining showed that the mucosal strips had severe structural damage in the cytokines-only group but not in the incubation-control group (P < 0.01). Compared to the cytokines-only group, crypt damage was significantly decreased in groups receiving cytokines with inhibitors ((10)Panx1, A438079, or (10)Panx1 + A438079, P < 0.05). The immunoreactive signals of tight junction protein zonula occludens-1 (ZO-1) were abundant in all control tissues but were significantly disrupted and lost in the cytokines-only group (P < 0.01). The diminished ZO-1 immunoreactivity induced by cytokines was prevented in the presence of (10)Panx1 (P = 0.04). Likewise, (10)Panx1 significantly attenuated the cytokines-evoked increase in paracellular permeability of Caco-2 cells. Although the inhibition of P2X7R activity by A438079 diminished cytokines-induced crypt damage, its effect on the maintenance of ZO-1 immunoreactivity and Caco-2 epithelial cell integrity was less evident. Conclusion: The blockade of Panx1 and P2X7R reduced the inflammatory cytokines-induced crypt damage, loss of tight junctions and increase in cell permeability. Thus, Panx1 and P2X7R may have roles in causing mucosal damage, a common clinical feature of inflammatory bowel disease.

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Title: Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa
Authors: Erica F Diezmos (Author) - University of New South Wales
Irit Markus (Author) - University of New South Wales
D S Perera (Author) - Sydney Colorectal Associates
Steven Gan (Author) - Sydney Colorectal Associates
Li Zhang (Author) - University of New South Wales
Shaun L Sandow (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and Engineering
Paul P Bertrand (Author) - University of New South Wales
Lu Liu (Author) - University of New South Wales
Publication details: Frontiers in Pharmacology, Vol.9, 865; 14
Publisher: Frontiers Research Foundation
Date published: 2018
DOI: 10.3389/fphar.2018.00865
ISSN: 1663-9812
Copyright note: Copyright © 2018 Diezmos, Markus, Perera, Gan, Zhang, Sandow, Bertrand and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Organisation Unit: School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450890402621
Output Type: Journal article

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