Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt

2004 ◽  
Vol 287 (1) ◽  
pp. G286-G298 ◽  
Author(s):  
Hedy H. Ginzberg ◽  
Patrick T. Shannon ◽  
Tomoko Suzuki ◽  
Ouyang Hong ◽  
Eric Vachon ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Survival ◽  
Membrane Permeability ◽  
Mitochondrial Membrane ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Mitochondrial Membrane Permeability ◽  
Leukocyte Elastase ◽  
Epithelial Cell Apoptosis ◽  
Induced Apoptosis

During acute inflammation, neutrophil-mediated injury to epithelium may lead to disruption of epithelial function, including the induction of epithelial apoptosis. Herein, we report the effects of neutrophil transmigration and of purified leukocyte elastase on epithelial cell survival. Neutrophil transmigration induced apoptosis of epithelial cells [control monolayers: 5 ± 1 cells/25 high-power fields (HPF) vs. neutrophil-treated monolayers: 29 ± 10 cells/HPF, P < 0.05, n = 3 as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay] as did low concentrations (0.1 U/ml) of purified leukocyte elastase (control monolayers: 6.4 ± 2.5% apoptotic vs. elastase: 26.2 ± 2.9% apoptotic, P < 0.05, as determined by cytokeratin 18 cleavage). Treatment with elastase resulted in decreased mitochondrial membrane potential, release of cytochrome c to the cytosol, and cleavage of caspases-9 and -3 as determined by Western blot analysis, implicating altered mitochondrial membrane permeability as a primary mechanism for elastase-induced apoptosis. Additionally, incubation of epithelial cells with leukocyte elastase resulted in an early increase followed by a decrease in the phosphorylation of epithelial Akt, a serine/threonine kinase important in cell survival. Inhibition of epithelial Akt before elastase treatment potentiated epithelial cell apoptosis, suggesting that the initial activation of Akt represents a protective response by the epithelial cells to the proapoptotic effects of leukocyte elastase. Taken together, these observations suggest that epithelial cells exhibit a dual response to cellular stress imposed by leukocyte elastase with a proapoptotic response mediated via early alterations in mitochondrial membrane permeability countered by activation of the survival pathway involving Akt.

Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-γ and Fas

1997 ◽  
Vol 273 (5) ◽  
pp. L921-L929 ◽  
Author(s):  
Long-Ping Wen ◽  
Kamyar Madani ◽  
Jimothy A. Fahrni ◽  
Steven R. Duncan ◽  
Glenn D. Rosen
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Cell Apoptosis ◽  
Inhibitor Of Apoptosis ◽  
Induced Expression ◽  
Lung Epithelial ◽  
Epithelial Cell Apoptosis ◽  
Ifn Γ ◽  
Induced Apoptosis

Lung epithelium plays a central role in modulation of the inflammatory response and in lung repair. Airway epithelial cells are targets in asthma, viral infection, acute lung injury, and fibrotic lung disease. Activated T lymphocytes release cytokines such as interferon-γ (IFN-γ) that can cooperate with apoptotic signaling pathways such as the Fas-APO-1 pathway to induce apoptosis of damaged epithelial cells. We report that IFN-γ alone and in combination with activation of the Fas pathway induced apoptosis in A549 lung epithelial cells. Interestingly, the corticosteroid dexamethasone was the most potent inhibitor of IFN-γ- and IFN-γ plus anti-Fas-induced apoptosis. IFN-γ induced expression of an effector of apoptosis, the cysteine protease interleukin-1β-converting enzyme, in A549 cells. Dexamethasone, in contrast, induced expression of an inhibitor of apoptosis, human inhibitor of apoptosis (hIAP-1), also known as cIAP2. We suggest that the inhibition of epithelial cell apoptosis by corticosteroids may be one mechanism by which they suppress the inflammatory response.

scholarly journals Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival

2000 ◽  
Vol 97 (9) ◽  
pp. 4666-4671 ◽  
Author(s):  
M. G. Vander Heiden ◽  
N. S. Chandel ◽  
X. X. Li ◽  
P. T. Schumacker ◽  
M. Colombini ◽  
...  
Keyword(s):  
Cell Survival ◽  
Membrane Permeability ◽  
Mitochondrial Membrane ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Membrane Permeability

Interferon-γ promotes double-stranded RNA-induced TLR3-dependent apoptosis via upregulation of transcription factor Runx3 in airway epithelial cells

2016 ◽  
Vol 311 (6) ◽  
pp. L1101-L1112 ◽  
Author(s):  
Huachen Gan ◽  
Qin Hao ◽  
Steven Idell ◽  
Hua Tang
Keyword(s):  
Transcription Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Apoptosis ◽  
Airway Epithelial Cells ◽  
Poly I:C ◽  
Airway Epithelial ◽  
Epithelial Cell Apoptosis ◽  
Induced Apoptosis ◽  
Viral Respiratory

Viral respiratory tract infections are the most common illness in humans. Infection of the respiratory viruses results in accumulation of viral replicative double-stranded RNA (dsRNA), which is one of the important components of infecting viruses for the induction of lung epithelial cell apoptosis and innate immune response, including the production of interferon (IFN). In the present study, we have investigated the regulation of dsRNA-induced airway epithelial cell apoptosis by IFN. We found that transcription factor Runx3 was strongly induced by type-II IFNγ, slightly by type-III IFNλ, but essentially not by type-I IFNα in airway epithelial cells. IFNγ-induced expression of Runx3 was predominantly mediated by JAK-STAT1 pathway and partially by NF-κB pathway. Interestingly, Runx3 can be synergistically induced by IFNγ with a synthetic analog of viral dsRNA polyinosinic-polycytidylic acid [poly(I:C)] or tumor necrosis factor-α (TNFα) through both JAK-STAT1 and NF-κB pathways. We further found that dsRNA poly(I:C)-induced apoptosis of airway epithelial cells was mediated by dsRNA receptor toll-like receptor 3 (TLR3) and was markedly augmented by IFNγ through the enhanced expression of TLR3 and subsequent activation of both extrinsic and intrinsic apoptosis pathways. Last, we demonstrated that upregulation of Runx3 by IFNγ promoted TLR3 expression, thus amplifying the dsRNA-induced apoptosis in airway epithelial cells. These novel findings indicate that IFNγ promotes dsRNA-induced TLR3-dependent apoptosis via upregulation of transcription factor Runx3 in airway epithelial cells. Findings from our study may provide new insights into the regulation of airway epithelial cell apoptosis by IFNγ during viral respiratory tract infection.

scholarly journals Brucea javanica Leaf Extract Induced Apoptosis in Human Oral Squamous Cell Carcinoma (HSC2) Cells by Attenuation of Mitochondrial Membrane Permeability

2015 ◽  
Vol 7 (2) ◽  
pp. 107
Author(s):  
Britanto Dani Wicaksono ◽  
Enos Tangkearung ◽  
Ferry Sandra
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Membrane Permeability ◽  
Squamous Cell ◽  
Mitochondrial Membrane ◽  
Leaf Extract ◽  
Mitochondrial Membrane Permeability ◽  
Brucea Javanica ◽  
Induced Apoptosis

BACKGROUND: Brucea javanica extract has been reported to have anti-proliferative and cell death induction activities. B. javanica extract was reported to induce apoptosis through caspase cascade. Most of investigated B. javanica extracts were derived from seeds and fruits, or commercially available oil emulsion. Therefore we conducted a study on B. javanica leaf extract (BJLE) in oral cancer cells.METHODS: B. javanica leaves were collected, identified, minced, dried, extracted with distilled ethanol at room temperature for 24 hours, filtered and evaporated. Resulted BJLE was stored at 4°C. Human oral squamous cell carcinoma (HSC)-2 cells were fasted for 12 hours and treated with BJLE in various concentrations for 24 hours. Cells were then quantified with 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide (MTT) assay, demonstrated with 4',6'-diamidino-2-phenylindole (DAPI) staining. To find out mitochondrial membrane permeability (MMP), mitochondrial membrane potential (ΔΨM) was analyzed.RESULTS: BJLE reduced percentage of viable HSC-2 cells in a concentration dependent manner. BJLE induced apoptosis in HSC-2 cells. With treatment of 50 μg/ml BJLE, fragmented nuclei were seen. ΔΨM of HSC-2 cells treated with 50 μg/ml BJLE were shifted to the left, meaning that BJLE induced reduction of ΔΨM and attenuation of MMP.CONCLUSION: Our results suggested that BJLE could induce apoptosis by attenuating MMP.KEYWORDS: Brucea javanica, leaf, apoptosis, HSC-2, MTT, DAPI, mitochondria, permeability

scholarly journals TNF-α converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival

2011 ◽  
Vol 301 (2) ◽  
pp. G338-G346 ◽  
Author(s):  
Valda C. Hilliard ◽  
Mark R. Frey ◽  
Peter J. Dempsey ◽  
Richard M. Peek ◽  
D. Brent Polk
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Ligand Binding ◽  
Cell Survival ◽  
Neutralizing Antibodies ◽  
Tissue Injury ◽  
Converting Enzyme ◽  
Tnf Α ◽  
Induced Apoptosis

Disruption of intestinal epithelial homeostasis, including enhanced apoptosis, is a hallmark of inflammatory bowel disease (IBD). We have recently shown that tumor necrosis factor (TNF) increases the kinase activity of ErbB4, a member of the epidermal growth factor receptor family that is elevated in mucosa of IBD patients and that promotes colon epithelial cell survival. In this study, we tested the hypothesis that TNF transactivates ErbB4 through TNF-α converting enzyme (TACE)-mediated ligand release and that this transactivation is necessary to protect colonic epithelial cells from cytokine-induced apoptosis. Using neutralizing antibodies, we show that heparin-binding EGF-like growth factor (HB-EGF) is required for ErbB4 phosphorylation in response to TNF. Pharmacological or genetic inhibition of the metalloprotease TACE, which mediates HB-EGF release from cells, blocked TNF-induced ErbB4 activation. MEK, but not Src or p38, was also required for transactivation. TACE activity and ligand binding were required for ErbB4-mediated antiapoptotic signaling; whereas mouse colon epithelial cells expressing ErbB4 were resistant to TNF-induced apoptosis, TACE inhibition or blockade of ErbB4 ligand binding reversed the survival advantage. We conclude that TNF transactivates ErbB4 through TACE-dependent HB-EGF release, thus protecting colon epithelial cells from cytokine-induced apoptosis. These findings have important implications for understanding how ErbB4 protects the colon from apoptosis-induced tissue injury in inflammatory conditions such as IBD.

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