TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death

ABSTRACT Inhalation of ricin toxin is associated with the onset of acute respiratory distress syndrome (ARDS), characterized by hemorrhage, inflammatory exudates, and tissue edema, as well as the nearly complete destruction of the lung epithelium. Here we report that the Calu-3 human airway epitheli...

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Autores principales:	Yinghui Rong, Jennifer Westfall, Dylan Ehrbar, Timothy LaRocca, Nicholas J. Mantis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	bioterrorism cytokines epithelial cells inflammation lung defense toxins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9690467bf65245f5b7c42182c82a6e1e
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spelling	oai:doaj.org-article:9690467bf65245f5b7c42182c82a6e1e2021-11-15T15:22:26ZTRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death10.1128/mSphere.00399-182379-5042https://doaj.org/article/9690467bf65245f5b7c42182c82a6e1e2018-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00399-18https://doaj.org/toc/2379-5042ABSTRACT Inhalation of ricin toxin is associated with the onset of acute respiratory distress syndrome (ARDS), characterized by hemorrhage, inflammatory exudates, and tissue edema, as well as the nearly complete destruction of the lung epithelium. Here we report that the Calu-3 human airway epithelial cell line is relatively impervious to the effects of ricin, with little evidence of cell death even upon exposure to microgram amounts of toxin. However, the addition of exogenous soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL; CD253) dramatically sensitized Calu-3 cells to ricin-induced apoptosis. Calu-3 cell killing in response to ricin and TRAIL exposure was partially inhibited by caspase-8 and caspase-3/7 inhibitors, consistent with involvement of extrinsic apoptotic pathways in cell death. We employed nCounter Technology to define the transcriptional response of Calu-3 cells to ricin, TRAIL, and the combination of ricin plus TRAIL. An array of genes associated with inflammation and cell death were significantly upregulated upon treatment with ricin toxin and were further amplified upon addition of TRAIL. Of particular note was interleukin-6 (IL-6), whose expression in Calu-3 cells increased 300-fold upon ricin treatment and more than 750-fold upon ricin and TRAIL treatment. IL-6 secretion by Calu-3 cells was confirmed by cytometric bead array analysis. On the basis of these finding, we speculate that the severe airway epithelial cell damage observed in animal models following ricin exposure is a result of a positive-feedback loop driven by proinflammatory cytokines such as TRAIL and IL-6. IMPORTANCE Ricin toxin is a biothreat agent that is particularly damaging to lung tissue following inhalation. A hallmark of ricin exposure is widespread inflammation and concomitant destruction of the airway epithelium. In this study, we investigated the possible interaction between ricin and known proinflammatory cytokines associated with lung tissue. Using an established human airway epithelial cell line, we demonstrate that epithelial cell killing by ricin is significantly enhanced in the presence of the proinflammatory cytokine known as TRAIL (CD253). Moreover, epithelial cells that are simultaneously exposed to ricin and TRAIL produced large amounts of secondary proinflammatory signals, including IL-6, which in the context of the lung would be expected to exacerbate toxin-induced tissue damage. Our results suggest that therapies designed to neutralize proinflammatory cytokines such as TRAIL and IL-6 may limit the bystander damage associated with ricin exposure.Yinghui RongJennifer WestfallDylan EhrbarTimothy LaRoccaNicholas J. MantisAmerican Society for Microbiologyarticlebioterrorismcytokinesepithelial cellsinflammationlung defensetoxinsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	bioterrorism cytokines epithelial cells inflammation lung defense toxins Microbiology QR1-502
spellingShingle	bioterrorism cytokines epithelial cells inflammation lung defense toxins Microbiology QR1-502 Yinghui Rong Jennifer Westfall Dylan Ehrbar Timothy LaRocca Nicholas J. Mantis TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
description	ABSTRACT Inhalation of ricin toxin is associated with the onset of acute respiratory distress syndrome (ARDS), characterized by hemorrhage, inflammatory exudates, and tissue edema, as well as the nearly complete destruction of the lung epithelium. Here we report that the Calu-3 human airway epithelial cell line is relatively impervious to the effects of ricin, with little evidence of cell death even upon exposure to microgram amounts of toxin. However, the addition of exogenous soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL; CD253) dramatically sensitized Calu-3 cells to ricin-induced apoptosis. Calu-3 cell killing in response to ricin and TRAIL exposure was partially inhibited by caspase-8 and caspase-3/7 inhibitors, consistent with involvement of extrinsic apoptotic pathways in cell death. We employed nCounter Technology to define the transcriptional response of Calu-3 cells to ricin, TRAIL, and the combination of ricin plus TRAIL. An array of genes associated with inflammation and cell death were significantly upregulated upon treatment with ricin toxin and were further amplified upon addition of TRAIL. Of particular note was interleukin-6 (IL-6), whose expression in Calu-3 cells increased 300-fold upon ricin treatment and more than 750-fold upon ricin and TRAIL treatment. IL-6 secretion by Calu-3 cells was confirmed by cytometric bead array analysis. On the basis of these finding, we speculate that the severe airway epithelial cell damage observed in animal models following ricin exposure is a result of a positive-feedback loop driven by proinflammatory cytokines such as TRAIL and IL-6. IMPORTANCE Ricin toxin is a biothreat agent that is particularly damaging to lung tissue following inhalation. A hallmark of ricin exposure is widespread inflammation and concomitant destruction of the airway epithelium. In this study, we investigated the possible interaction between ricin and known proinflammatory cytokines associated with lung tissue. Using an established human airway epithelial cell line, we demonstrate that epithelial cell killing by ricin is significantly enhanced in the presence of the proinflammatory cytokine known as TRAIL (CD253). Moreover, epithelial cells that are simultaneously exposed to ricin and TRAIL produced large amounts of secondary proinflammatory signals, including IL-6, which in the context of the lung would be expected to exacerbate toxin-induced tissue damage. Our results suggest that therapies designed to neutralize proinflammatory cytokines such as TRAIL and IL-6 may limit the bystander damage associated with ricin exposure.
format	article
author	Yinghui Rong Jennifer Westfall Dylan Ehrbar Timothy LaRocca Nicholas J. Mantis
author_facet	Yinghui Rong Jennifer Westfall Dylan Ehrbar Timothy LaRocca Nicholas J. Mantis
author_sort	Yinghui Rong
title	TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
title_short	TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
title_full	TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
title_fullStr	TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
title_full_unstemmed	TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death
title_sort	trail (cd253) sensitizes human airway epithelial cells to toxin-induced cell death
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/9690467bf65245f5b7c42182c82a6e1e
work_keys_str_mv	AT yinghuirong trailcd253sensitizeshumanairwayepithelialcellstotoxininducedcelldeath AT jenniferwestfall trailcd253sensitizeshumanairwayepithelialcellstotoxininducedcelldeath AT dylanehrbar trailcd253sensitizeshumanairwayepithelialcellstotoxininducedcelldeath AT timothylarocca trailcd253sensitizeshumanairwayepithelialcellstotoxininducedcelldeath AT nicholasjmantis trailcd253sensitizeshumanairwayepithelialcellstotoxininducedcelldeath
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TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death

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