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

2018 ◽  
Author(s):  
Yinghui Rong ◽  
Jennifer Westfall ◽  
Dylan Ehrbar ◽  
Timothy LaRocca ◽  
Nicholas J. Mantis
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Airway Epithelial Cell ◽  
Cell Damage ◽  
Transcriptional Response ◽  
Airway Epithelial Cells ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Ricin Toxin ◽  
Human Airway

ABSTRACTInhalation 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 near 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 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 was reduced upon the addition of caspase-8 and caspase-3/7 inhibitors, but not caspase 9 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 up regulated upon treatment with ricin toxin, and further amplified upon addition of TRAIL. Of particular note was 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. Based on 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 pro-inflammatory cytokines like TRAIL and IL-6.

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

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Yinghui Rong ◽  
Jennifer Westfall ◽  
Dylan Ehrbar ◽  
Timothy LaRocca ◽  
Nicholas J. Mantis
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Line ◽  
Proinflammatory Cytokines ◽  
Airway Epithelial Cell ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Ricin Toxin ◽  
Human Airway

ABSTRACTInhalation 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 solubletumornecrosisfactor (TNF)-relatedapoptosis-inducingligand (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.IMPORTANCERicin 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.

Prostaglandin E2-induced interleukin-6 release by a human airway epithelial cell line

2001 ◽  
Vol 280 (1) ◽  
pp. L127-L133 ◽  
Author(s):  
S. Tavakoli ◽  
M. J. Cowan ◽  
T. Benfield ◽  
C. Logun ◽  
J. H. Shelhamer
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Airway Epithelial Cell ◽  
Epithelial Cell Line ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Airway Epithelial ◽  
Human Airway ◽  
Human Airway Epithelial Cell ◽  
Cell Release

Human airway epithelial cell release of interleukin (IL)-6 in response to lipid mediators was studied in an airway cell line (BEAS-2B). Prostaglandin (PG) E2(10−7M) treatment caused an increase in IL-6 release at 2, 4, 8, and 24 h. IL-6 release into the culture medium at 24 h was 3,396 ± 306 vs. 1,051 ± 154 pg/ml (PGE2-treated cells vs. control cells). PGE2(10−7to 10−10M) induced a dose-related increase in IL-6 release at 24 h. PGF2α(10−6M) treatment caused a similar effect to that of PGE2(10−7M). PGE2analogs with relative selectivity for PGE2receptor subtypes were studied. Sulprostone, a selective agonist for the EP-3 receptor subtype had no effect on IL-6 release. 11-Deoxy-16,16-dimethyl-PGE2, an EP-2/4 agonist, and 17-phenyl trinor PGE2, an agonist selective for the EP-1 > EP-3 receptor subtype (10−6to 10−8M), caused dose-dependent increases in IL-6 release. 8-Bromo-cAMP treatment resulted in dose-related increases in IL-6 release. RT-PCR of BEAS-2B cell mRNA demonstrated mRNA for EP-1, EP-2, and EP-4 receptors. After PGE2treatment, increases in IL-6 mRNA were noted at 4 and 18 h. Therefore, PGE2increases airway epithelial cell IL-6 production and release.

Paraoxonase-2 deficiency enhancesPseudomonas aeruginosaquorum sensing in murine tracheal epithelia

2007 ◽  
Vol 292 (4) ◽  
pp. L852-L860 ◽  
Author(s):  
David A. Stoltz ◽  
Egon A. Ozer ◽  
Carey J. Ng ◽  
Janet M. Yu ◽  
Srinivasa T. Reddy ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Quorum Sensing ◽  
Airway Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Tracheal Epithelial Cells ◽  
Human Airway ◽  
Tracheal Epithelial

Pseudomonas aeruginosa is an important cause of nosocomial infections and is frequently present in the airways of cystic fibrosis patients. Quorum sensing mediates P. aeruginosa's virulence and biofilm formation through density-dependent interbacterial signaling with autoinducers. N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is the major autoinducer in P. aeruginosa. We have previously shown that human airway epithelia and paraoxonases (PONs) degrade 3OC12-HSL. This study investigated the role of PON1, PON2, and PON3 in airway epithelial cell inactivation of 3OC12-HSL. All three PONs were present in murine tracheal epithelial cells, with PON2 and PON3 expressed at the highest levels. Lysates of tracheal epithelial cells from PON2, but not PON1 or PON3, knockout mice had impaired 3OC12-HSL inactivation compared with wild-type mice. In contrast, PON1-, PON2-, or PON3-targeted deletions did not affect 3OC12-HSL degradation by intact epithelia. Overexpression of PON2 enhanced 3OC12-HSL degradation by human airway epithelial cell lysates but not by intact epithelia. Finally, using a quorum-sensing reporter strain of P. aeruginosa, we found that quorum sensing was enhanced in PON2-deficient airway epithelia. In summary, these results show that loss of PON2 impairs 3OC12-HSL degradation by airway epithelial cells and suggests that diffusion of 3OC12-HSL into the airway cells can be the rate-limiting step for degradation of the molecule.

15-Deoxy-Δ12,14-Prostaglandin J2 Induces IL-8 and GM-CSF in a Human Airway Epithelial Cell Line (NCI-H292)

2009 ◽  
Vol 149 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Takahito Chiba ◽  
Shigeharu Ueki ◽  
Wataru Ito ◽  
Hikari Kato ◽  
Masahide Takeda ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Airway Epithelial Cell ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Gm Csf ◽  
Human Airway ◽  
Human Airway Epithelial Cell

Regulation of human airway epithelial cell IL-8 expression by MAP kinases

2002 ◽  
Vol 283 (4) ◽  
pp. L690-L699 ◽  
Author(s):  
Jing Li ◽  
Sreedharan Kartha ◽  
Svetlana Iasvovskaia ◽  
Alan Tan ◽  
Rajesh K. Bhat ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Map Kinases ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Dominant Negative ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Human Airway ◽  
Tnf Α ◽  
Precise Relationship

Recent studies indicate that maximal IL-8 protein expression requires activation of NF-κB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-κB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-κB, ERK, JNK, and p38 for TNF-α-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF-α induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF-κB, ERK, and JNK, but not p38, each decreased TNF-α-induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF-α-induced NF-κB transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF-α-induced activation of activator protein (AP)-1 promoter sequences, which together function as a basal level enhancer. JNK activation was also required for AP-1 transactivation. Finally, inhibition of p38 attenuated IL-8 protein abundance, suggesting that p38 regulates IL-8 expression in a posttranscriptional manner. We conclude that, in human airway epithelial cells, MAP kinases may regulate IL-8 promoter activity by NF-κB-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38).

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