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Bilirubin attenuates ER Stress-Mediated Inflammation, escalates Apoptosis and reduces Proliferation in the LS174T Colonic Epithelial Cell Line

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Gundamaraju, R, Vemuri, R ORCID: 0000-0002-3238-426X, Chong, WC, Bulmer, AC and Eri, R ORCID: 0000-0003-1688-8043 2019 , 'Bilirubin attenuates ER Stress-Mediated Inflammation, escalates Apoptosis and reduces Proliferation in the LS174T Colonic Epithelial Cell Line' , International journal of medical sciences, vol. 16, no. 1 , pp. 135-144 , doi: 10.7150/ijms.29134.

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Abstract

Mildly elevated serum unconjugated bilirubin (UCB) concentrations are associated with protection against disease conditions underpinned by cellular and metabolic stress. To determine the potential therapeutic efficacy of UCB we tested it in an in vitro model of gut inflammation. Tunicamycin TUN (10 µg/mL) was used to induce endoplasmic reticular stress (ERS) affecting N-glycosylation in LS174T cells. Cultured cells were investigated with addition of UCB at doses 0.1, 1 and 10µM (resulting in bilirubin:albumin ratios of 0.325-0.003)against ER stress-mediated effects including inflammation, cell survival (determined by apoptosis) and proliferation. Gene expression of ER stress markers (Grp78, Perk, XBP1 and ATF6) were evaluated in addition to cytokine concentrations in media after six hours of treatment. We then verified the potential role of UCB in executing programmed cell death via PARP, Caspase3 and Annexin V assays and further explored cell proliferation using the Click-iT EdU assay. A dose of 10µM UCB most potently reduced tunicamycin-mediated effects on enhanced UPR markers, inflammatory cytokines and proliferation; however all the doses (i.e.0.1-10µM) reduced the expression of ER stress and inflammatory markers Grp78, NLRP3, IL1-b, XBP1, PERK and ATF6. Furthermore, media concentrations of pro-inflammatory cytokines IL-8, IL-4 and TNFα decreased and the anti-inflammatory cytokine IL-10 increased (P<0.05). A dose of 10µM UCB initiated intrinsic apoptosis via Caspase 3 and in addition reduced cellular proliferation. Collectively, these data indicate that co treatment with UCB resulted in reducing ER stress response to TUN in gastrointestinal epithelial cells, reduced the subsequent inflammatory response, induced cancer cell death and decreased cellular proliferation. These data suggest that mildly elevated circulating or enteric UCB might protect against gastrointestinal inflammatory disorders.

Item Type: Article
Authors/Creators:Gundamaraju, R and Vemuri, R and Chong, WC and Bulmer, AC and Eri, R
Keywords: IBD, bilirubin, ER stress, apoptosis
Journal or Publication Title: International journal of medical sciences
Publisher: Ivyspring International Publisher
ISSN: 1449-1907
DOI / ID Number: 10.7150/ijms.29134
Copyright Information:

Copyright 2019 Ivyspring International Publisher. Licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) https://creativecommons.org/licenses/by-nc/4.0/

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