scholarly journals 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 ◽  
Vol 11 (8) ◽  
pp. 450 ◽  
Author(s):  
Hodges ◽  
Kempen ◽  
McCaig ◽  
Parker ◽  
Mantis ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Distinct Cell ◽  
Tnf Α ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

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.

TNF-α induces cytosolic phospholipase A2 expression via Jak2/PDGFR-dependent Elk-1/p300 activation in human lung epithelial cells

2014 ◽  
Vol 306 (6) ◽  
pp. L543-L551 ◽  
Author(s):  
Chuen-Mao Yang ◽  
I-Ta Lee ◽  
Pei-Ling Chi ◽  
Shin-Ei Cheng ◽  
Li-Der Hsiao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Growth Factor Receptor ◽  
Lung Epithelial Cells ◽  
Mapk Phosphorylation ◽  
Cytosolic Phospholipase ◽  
Tnf Α ◽  
Lung Epithelial ◽  
Phosphoinositide 3 Kinase ◽  
Human Lung Epithelial Cells

Cytosolic phospholipase A2 (cPLA2) plays a pivotal role in mediating agonist-induced arachidonic acid release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-α (TNF-α). However, the mechanisms underlying TNF-α-induced cPLA2 expression in human lung epithelial cells (HPAEpiCs) were not completely understood. Here, we demonstrated that TNF-α induced cPLA2 mRNA and protein expression, promoter activity, and PGE2 secretion in HPAEpiCs. These responses induced by TNF-α were inhibited by pretreatment with the inhibitor of Jak2 (AG490), platelet-derived growth factor receptor (PDGFR) (AG1296), phosphoinositide 3 kinase (PI3K) (LY294002), or MEK1/2 (PD98059) and transfection with siRNA of Jak2, PDGFR, Akt, or p42. We showed that TNF-α markedly stimulated Jak2, PDGFR, Akt, and p42/p44 MAPK phosphorylation, which were attenuated by their respective inhibitors. Moreover, TNF-α stimulated Akt activation via a Jak2/PDGFR pathway in HPAEpiCs. In addition, TNF-α-induced p42/p44 MAPK phosphorylation was reduced by AG1296 or LY294002. On the other hand, TNF-α could induce Akt and p42/p44 MAPK translocation from the cytosol into the nucleus, which was inhibited by AG490, AG1296, or LY294002. Finally, we showed that TNF-α stimulated Elk-1 phosphorylation, which was reduced by LY294002 or PD98059. We also observed that TNF-α time dependently induced p300/Elk-1 and p300/Akt complex formation in HPAEpiCs, which was reduced by AG490, AG1296, or LY294002. The activity of cPLA2 protein upregulated by TNF-α was reflected on the PGE2 release, which was reduced by AG490, AG1296, LY294002 , or PD98059. Taken together, these results demonstrated that TNF-α-induced cPLA2 expression and PGE2 release were mediated through a Jak2/PDGFR/PI3K/Akt/p42/p44 MAPK/Elk-1 pathway in HPAEpiCs.

scholarly journals Receptor Interacting Protein-2 Plays a Critical Role in Human Lung Epithelial Cells Survival in Response to Fas-Induced Cell-Death

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e92731 ◽  
Author(s):  
Mohd. Akhlakur Rahman ◽  
Kruthika Sundaram ◽  
Srabani Mitra ◽  
Mikhail A. Gavrilin ◽  
Mark D. Wewers
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Human Lung ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Interacting Protein ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

scholarly journals SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Hua Geng ◽  
Saravanan Subramanian ◽  
Longtao Wu ◽  
Heng-Fu Bu ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Viral Infection ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Accessory Protein ◽  
Epithelial Cell Proliferation ◽  
Lung Epithelial

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8SARS-CoV-2) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8SARS-CoV-2 and its role in the regulation of human lung epithelial cell proliferation and antiviral immunity. Using live imaging and immunofluorescent staining analyses, we found that ectopically expressed ORF8SARS-CoV-2 forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8SARS-CoV-2 possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8SARS-CoV-2 expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8SARS-CoV-2 aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8SARS-CoV-2 in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8SARS-CoV-2 attenuated the induction of antiviral molecules by IFNγ but not by IFNβ in lung epithelial cells. Taken together, ORF8SARS-CoV-2 is a unique viral accessory protein that forms aggregates when expressing in lung epithelial cells. It potently inhibits the expression of lung cellular anti-viral proteins at baseline and in response to IFNγ in lung epithelial cells, which may facilitate SARS-CoV-2 escape from the host antiviral innate immune response during early viral infection. In addition, it seems that formation of ORF8SARS-CoV-2 aggregate is independent from the viral infection. Thus, it would be interesting to examine whether any COVID-19 patients exhibit persistent ORF8 SARS-CoV-2 expression after recovering from SARS-CoV-2 infection. If so, the pathogenic effect of prolonged ORF8SARS-CoV-2 expression and its association with post-COVID symptoms warrant investigation in the future.

scholarly journals Soluble extracellular Klotho decreases sensitivity to cigarette smoke induced cell death in human lung epithelial cells

2015 ◽  
Vol 29 (7) ◽  
pp. 1647-1652 ◽  
Author(s):  
David J. Blake ◽  
Caitlyn M. Reese ◽  
Mario Garcia ◽  
Elizabeth A. Dahlmann ◽  
Alexander Dean
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

scholarly journals Peptidome analysis of umbilical cord mesenchymal stem cell (hUC-MSC) conditioned medium from preterm and term infants

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Wang ◽  
Lin Zhang ◽  
Yun Wu ◽  
Rongping Zhu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Differentially Expressed ◽  
Tandem Mass ◽  
Tnf Α ◽  
Lung Epithelial ◽  
Precursor Proteins ◽  
Human Lung Epithelial Cells

Abstract Background The therapeutic role of mesenchymal stem cells (MSCs) has been widely confirmed in several animal models of premature infant diseases. Micromolecule peptides have shown promise for the treatment of premature infant diseases. However, the potential role of peptides secreted from MSCs has not been studied. The purpose of this study is to help to broaden the knowledge of the hUC-MSC secretome at the peptide level through peptidomic profile analysis. Methods We used tandem mass tag (TMT) labeling technology followed by tandem mass spectrometry to compare the peptidomic profile of preterm and term umbilical cord MSC (hUC-MSC) conditioned medium (CM). Gene Ontology (GO) enrichment analysis and ingenuity pathway analysis (IPA) were conducted to explore the differentially expressed peptides by predicting the functions of their precursor proteins. To evaluate the effect of candidate peptides on human lung epithelial cells stimulated by hydrogen peroxide (H2O2), quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were, respectively, adopted to detect inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression levels at the mRNA and protein levels. Results A total of 131 peptides derived from 106 precursor proteins were differentially expressed in the preterm hUC-MSC CM compared with the term group, comprising 37 upregulated peptides and 94 downregulated peptides. Bioinformatics analysis showed that these differentially expressed peptides may be associated with developmental disorders, inflammatory response, and organismal injury. We also found that peptides 7118TGAKIKLVGT7127 derived from MUC19 and 508AAAAGPANVH517 derived from SIX5 reduced the expression levels of TNF-α, IL-1β, and IL-6 in H2O2-treated human lung epithelial cells. Conclusions In summary, this study provides further secretomics information on hUC-MSCs and provides a series of peptides that might have antiinflammatory effects on pulmonary epithelial cells and contribute to the prevention and treatment of respiratory diseases in premature infants.

scholarly journals Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

2020 ◽  
Author(s):  
Yu Wang ◽  
Lin Zhang ◽  
Yun Wu ◽  
Rongping Zhu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Differentially Expressed ◽  
Tandem Mass ◽  
Tnf Α ◽  
Lung Epithelial ◽  
Precursor Proteins ◽  
Human Lung Epithelial Cells

Abstract Background: The therapeutic role of mesenchymal stem cells (MSCs) has been widely confirmed in several animal models of premature infant diseases. Micromolecule peptides have shown promise for the treatment of premature infant diseases. However, the potential role of peptides secreted from MSCs has not been studied. The purpose of this study is to helps to broaden the knowledge of the hUC-MSC secretome at the peptide level through peptidomic profile analysis.Methods: We used tandem mass tag (TMT) labeling technology followed by tandem mass spectrometry to compare the peptidomic profile of preterm and term umbilical cord MSC (hUC-MSC) conditioned medium (CM). Gene Ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA) were conducted to explore the differentially expressed peptides by predicting the functions of their precursor proteins. To evaluate the effect of candidate peptides on human lung epithelial cells stimulated by hydrogen peroxide (H2O2), quantitative real-time PCR (qRT-PCR), western blot analysis and enzyme-linked immunosorbent assay (ELISA) were respectively adopted to detect inflammatory cytokines (TNF-α, IL-1β and IL-6) expression levels at the mRNA and protein levels,Results: A total of 131 peptides derived from 106 precursor proteins were differentially expressed in the preterm hUC-MSC CM compared with the term group, comprising 37 up-regulated peptides and 94 down-regulated peptides. Bioinformatics analysis showed that these differentially expressed peptides may be associated with developmental disorders, inflammatory response and organismal injury. We also found that peptides 7118TGAKIKLVGT7127 derived from MUC19 and 508AAAAGPANVH517 derived from SIX5 reduced the expression levels of TNF-α, IL-1β and IL-6 in H2O2-treated human lung epithelial cells.Conclusions: In summary, this study provides further secretomics information on hUC-MSCs and provides a series of peptides that might have antiinflammatory effects on pulmonary epithelial cells and contribute to the prevention and treatment of respiratory diseases in premature infants.

Sign in / Sign up

Export Citation Format

Share Document