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Intracellular Transport and Cytotoxicity of the Protein Toxin Ricin
Article

TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

1
Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
2
Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Received: 19 June 2019 / Revised: 19 July 2019 / Accepted: 28 July 2019 / Published: 1 August 2019
(This article belongs to the Special Issue Ricin Toxins)
Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule’s known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL. View Full-Text
Keywords: ricin; toxins; cytokines; toxin-mediated diseases; apoptosis; cathepsin; tumor necrosis factor; fas; caspases ricin; toxins; cytokines; toxin-mediated diseases; apoptosis; cathepsin; tumor necrosis factor; fas; caspases
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MDPI and ACS Style

Hodges, A.L.; Kempen, C.G.; McCaig, W.D.; Parker, C.A.; Mantis, N.J.; LaRocca, T.J. TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin. Toxins 2019, 11, 450. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11080450

AMA Style

Hodges AL, Kempen CG, McCaig WD, Parker CA, Mantis NJ, LaRocca TJ. TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin. Toxins. 2019; 11(8):450. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11080450

Chicago/Turabian Style

Hodges, Alexa L., Cody G. Kempen, William D. McCaig, Cory A. Parker, Nicholas J. Mantis, and Timothy J. LaRocca 2019. "TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin" Toxins 11, no. 8: 450. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11080450

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