Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium

ABSTRACT Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with lung epithelial cells. Apoptosis of lung epithelium is involved in some bacterial lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H2O2. Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin- and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.

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Inhibition of PI3Kδ Differentially Regulates Poly I:C– and Human Metapneumovirus–Induced PD–L1 and PD–L2 Expression in Human Bronchial Epithelial Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.767666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tomohiro Ogawa ◽

Keiko Kan-o ◽

Ayaka Shiota ◽

Akitaka Fujita ◽

Yumiko Ishii ◽

...

Keyword(s):

Cell Death ◽

Epithelial Cells ◽

Programmed Cell Death ◽

Bronchial Epithelial Cells ◽

Human Metapneumovirus ◽

Poly I:C ◽

Type I ◽

Bronchial Epithelial ◽

Double Stranded Rna ◽

Programmed Cell Death 1

Bronchial epithelial cells are front sentinels eliciting innate and adaptive immunity to respiratory viral pathogens. Recognition of viral double-stranded RNA induces antiviral interferon (IFN) responses in bronchial epithelial cells. Co-inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) were also induced on bronchial epithelial cells, which bind programmed cell death 1 on T cell and inhibit the function of virus-specific cytotoxic T lymphocyte. A previous study showed that antiviral type I IFN increased PD-L1 and PD-L2 expression in cultured melanoma cells. However, it remains unknown whether antiviral IFNs affect PD-L1 and PD-L2 expression in bronchial epithelial cells. In addition, we previously reported that inhibition of PI3Kδ signaling enhanced antiviral IFN responses in human primary bronchial epithelial cells (PBECs). Here we assessed the effect of exogenous IFNs or a selective PI3Kδ inhibitor IC87114 on PD-L1 and PD-L2 in PBECs stimulated with a synthetic double-stranded RNA poly I:C or human metapneumovirus. Treatment with IFNβ or IFNλ increased PD-L1 and PD-L2, and IFNβ or IFNλ treatment plus poly I:C further increased both expressions. Treatment with IC87114 or transfection with siRNA targeting PI3K p110δ enhanced poly I:C–induced gene and protein expression of PD-L2, whereas IC87114 suppressed poly I:C–induced PD-L1. IC87114 enhanced poly I:C–induced gene expression of IFNβ, IFNλ, and IFN-regulated genes via increased TBK1 and IRF3 phosphorylation. Transfection with siIRF3 counteracted the enhancement of poly I:C–induced PD-L2 by IC87114, whereas IC87114 suppressed poly I:C–induced PD-L1 regardless of transfection with siNC or siIRF3. Similar effects of IC87114 on PD-L1 and PD-L2 expression were observed in human metapneumovirus–infected PBECs. We showed for the first time that type I and type III IFNs induced the expression of PD-L1 and PD-L2 in PBECs. Our findings suggest that during viral infections, inhibition of PI3Kδ differentially regulates PD-L1 and PD-L2 expression in bronchial epithelial cells.

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Apoptosis in Hydra: function of HyBcl-2 like 4 and proteins of the transmembrane BAX inhibitor motif (TMBIM) containing family

The International Journal of Developmental Biology ◽

10.1387/ijdb.180199ab ◽

2019 ◽

Vol 63 (6-7) ◽

pp. 259-270 ◽

Cited By ~ 2

Author(s):

Mina Motamedi ◽

Laura Lindenthal ◽

Anita Wagner ◽

Margherita Kemper ◽

Jasmin Moneer ◽

...

Keyword(s):

Cell Death ◽

Plasma Membrane ◽

Epithelial Cells ◽

Programmed Cell Death ◽

Kinase Inhibitor ◽

Apoptotic Cell ◽

Family Members ◽

Sequence Comparisons ◽

Induced Apoptosis ◽

Related Proteins

Mechanisms of programmed cell death differ between animals, plants and fungi. In animals, apoptotic cell death depends on caspases and Bcl-2 family proteins. These protein families are only found in multicellular animals, including cnidarians, insects and mammals. In contrast, members of the TMBIM-family of transmembrane proteins are conserved across all eukaryotes. Sequence comparisons of cell death related proteins between phyla indicate strong conservation of the genes involved. However, often it is not known whether this is paralleled by conservation of function. Here we present the first study to support an anti-apoptotic function of Bcl-2 like proteins in the cnidarian Hydra within a physiological context. We used transgenic Hydra expressing GFP-tagged HyBcl-2-like 4 protein in epithelial cells. The protein was localised to mitochondria and able to protect Hydra epithelial cells from apoptosis induced by either the PI(3) kinase inhibitor wortmannin or by starvation. Moreover, we identified members of the TMBIM-family in Hydra including HyBax-Inhibitor-1, HyLifeguard-1a and -1b and HyLifeguard 4. Expressing these TMBIM-family members in Hydra and human HEK cells, we found HyBax-inhibitor-1 protein localised to ER-membranes and HyLifeguard-family members localised to the plasma membrane and Golgi-vesicles. Moreover, HyBax-inhibitor-1 protected human cells from camptothecin induced apoptosis. This work illustrates that the investigated Bcl-2- and TMBIM-family members represent evolutionarily conserved mitochondrial, ER, Golgi and plasma membrane proteins with anti-apoptotic functions. The participation of ER and Golgi proteins in the regulation of programmed cell death might be a very ancient feature.

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Lack of Correlation between Activation of Jun–NH2-terminal Kinase and Induction of Apoptosis after Detachment of Epithelial Cells

The Journal of Cell Biology ◽

10.1083/jcb.139.4.1017 ◽

1997 ◽

Vol 139 (4) ◽

pp. 1017-1023 ◽

Cited By ~ 80

Author(s):

Asim Khwaja ◽

Julian Downward

Keyword(s):

Cell Death ◽

Epithelial Cells ◽

Programmed Cell Death ◽

Mdck Cells ◽

Dominant Negative ◽

Signaling Proteins ◽

Direct Role ◽

Related Stress ◽

Induced Apoptosis ◽

Jnk Activation

Detachment of epithelial cells from the extracellular matrix leads to induction of programmed cell death, a process that has been termed “anoikis.” It has been reported recently that detachment of MDCK cells from matrix results in activation of Jun–NH2-terminal kinases (JNKs) and speculated that these stress activated protein kinases play a causal role in the induction of anoikis (Frisch, S.M., K. Vuori, D. Kelaita, and S. Sicks. 1996. J. Cell Biol. 135:1377–1382). We report here that although JNK is activated by detachment of normal MDCK cells, study of cell lines expressing activated signaling proteins usually controlled by Ras shows that stimulation of JNK fails to correlate with induction of anoikis. Activated phosphoinositide 3-OH kinase and activated PKB/Akt protect MDCK cells from detachment-induced apoptosis without suppressing JNK activation. Conversely, activated Raf and dominant negative SEK1, a JNK kinase, attenuate detachment-induced JNK activation without protecting from apoptosis. zVAD-fmk, a peptide inhibitor of caspases, prevents MDCK cell anoikis without affecting JNK activation. p38, a related stress-activated kinase, is also stimulated by detachment from matrix, but inhibition of this kinase with SB 203580 does not protect from anoikis. It is therefore unlikely that either JNK or p38 play a direct role in detachment-induced programmed cell death in epithelial cells.

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Study of programmed cell death in bovine herpesvirus 1 infected mdbk cells and the possible role of nitric oxide in this process

Acta Veterinaria Hungarica ◽

10.1556/avet.52.2004.3.5 ◽

2004 ◽

Vol 52 (3) ◽

pp. 287-297 ◽

Cited By ~ 4

Author(s):

Zafer Yazici ◽

Yasemin Baskin ◽

H. Baskin ◽

Ozlem Gecer ◽

I. Hakki Bahar ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Programmed Cell Death ◽

Bacterial Infections ◽

Caspase 3 ◽

Bovine Herpesvirus ◽

Bovine Herpesvirus 1 ◽

Mdbk Cells ◽

Herpesvirus 1 ◽

Induced Apoptosis

Bovine herpesvirus 1 (BHV-1) is the aetiological agent of many disease types and may predispose infected animals, possibly through immunosuppression, to secondary bacterial infections. Immunosuppression may directly be associated with the induction of programmed cell death (PCD) in some virus-infected cells. Nitric oxide (NO) has an important mediating role against fungal, bacterial, protozoal, viral pathogens and tumours. BHV-1 induced apoptosis between 0.5-3 h postinfection (PI) in MDBK cells; however, between 3 and 6 h PI the PCD response was found to be decreased. It was interesting to see that BHV-1 inhibited staurosporin-induced PCD after 1 h. These results showed similarities with those obtained from herpes simplex type 1 infections in human epithelial cells. PCD response decreased 1 h following caspase-3 inhibitor applications, whereas NO response increased 3 h following infection in the presence of caspase-8 and -9 inhibitory peptides. In conclusion, BHV-1 inhibited the staurosporin-induced apoptotic response and also the NO response. We propose that this inhibition is caspase-3 dependent.

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MicroRNA-760 resists ambient PM2.5-induced apoptosis in human bronchial epithelial cells through elevating heme-oxygenase 1 expression

Environmental Pollution ◽

10.1016/j.envpol.2021.117213 ◽

2021 ◽

Vol 284 ◽

pp. 117213

Author(s):

Lin Xu ◽

Qianwen Zhao ◽

Daochuan Li ◽

Jiao Luo ◽

Wanli Ma ◽

...

Keyword(s):

Epithelial Cells ◽

Heme Oxygenase ◽

Bronchial Epithelial Cells ◽

Heme Oxygenase 1 ◽

Human Bronchial Epithelial Cells ◽

Bronchial Epithelial ◽

Induced Apoptosis

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Cell Death and Metabolic Stress in Gymnodinium catenatum Induced by Allelopathy

Toxins ◽

10.3390/toxins13070506 ◽

2021 ◽

Vol 13 (7) ◽

pp. 506

Author(s):

Leyberth José Fernández-Herrera ◽

Christine Johanna Band-Schmidt ◽

Tania Zenteno-Savín ◽

Ignacio Leyva-Valencia ◽

Claudia Judith Hernández-Guerrero ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Protein Content ◽

Caspase 3 ◽

Cellular Stress ◽

Allelopathic Effect ◽

Sod Activity ◽

Free Media ◽

O2 Production ◽

Gymnodinium Catenatum

Allelopathy between phytoplankton species can promote cellular stress and programmed cell death (PCD). The raphidophyte Chattonella marina var. marina, and the dinoflagellates Margalefidinium polykrikoides and Gymnodinium impudicum have allelopathic effects on Gymnodinium catenatum; however, the physiological mechanisms are unknown. We evaluated whether the allelopathic effect promotes cellular stress and activates PCD in G. catenatum. Cultures of G. catenatum were exposed to cell-free media of C. marina var. marina, M. polykrikoides and G. impudicum. The mortality, superoxide radical (O2●−) production, thiobarbituric acid reactive substances (TBARS) levels, superoxide dismutase (SOD) activity, protein content, and caspase-3 activity were quantified. Mortality (between 57 and 79%) was registered in G. catenatum after exposure to cell-free media of the three species. The maximal O2●− production occurred with C. marina var. marina cell-free media. The highest TBARS levels and SOD activity in G. catenatum were recorded with cell-free media from G. impudicum. The highest protein content was recorded with cell-free media from M. polykrikoides. All cell-free media caused an increase in the activity of caspase-3. These results indicate that the allelopathic effect in G. catenatum promotes cell stress and caspase-3 activation, as a signal for the induction of programmed cell death.

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Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l10 ◽

2001 ◽

Vol 280 (1) ◽

pp. L10-L17 ◽

Cited By ~ 32

Author(s):

Han-Ming Shen ◽

Zhuo Zhang ◽

Qi-Feng Zhang ◽

Choon-Nam Ong

Keyword(s):

Reactive Oxygen Species ◽

Cell Death ◽

Alveolar Macrophages ◽

Caspase 3 ◽

Reactive Oxygen ◽

Parp Cleavage ◽

Oxygen Species ◽

Caspase Activation ◽

Caspase 9 ◽

Induced Apoptosis

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.

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Caspase-3-like activity and proteasome degradation in grapevine suspension cell cultures undergoing silver-induced programmed cell death

Journal of Plant Physiology ◽

10.1016/j.jplph.2018.12.003 ◽

2019 ◽

Vol 233 ◽

pp. 42-51 ◽

Cited By ~ 5

Author(s):

Antonio Filippi ◽

Marco Zancani ◽

Elisa Petrussa ◽

Enrico Braidot

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cell Cultures ◽

Caspase 3 ◽

Suspension Cell ◽

Proteasome Degradation ◽

Suspension Cell Cultures

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Sequential and rapid activation of select caspases during apoptosis of normal intestinal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.274.6.g1117 ◽

1998 ◽

Vol 274 (6) ◽

pp. G1117-G1124 ◽

Cited By ~ 20

Author(s):

Johannes Grossmann ◽

Susanne Mohr ◽

Eduardo G. Lapetina ◽

Claudio Fiocchi ◽

Alan D. Levine

Keyword(s):

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Cysteine Proteases ◽

Intestinal Epithelial ◽

Caspase Activation ◽

High Turnover ◽

Sequential Activation ◽

Caspase 6 ◽

Caspase Substrate ◽

Induced Apoptosis

Detachment-induced cell death (DICD) is considered to be one of the means by which intestinal epithelial cells (IEC) die of apoptosis as they reach the lumen and are shed. Caspases, a family of cysteine proteases, play a central role in initiating, amplifying, and executing apoptosis; however, the pattern of caspase activation in response to distinct apoptotic stimuli remains unknown. We investigated the kinetics of caspase activation during DICD in freshly isolated human IEC. DNA fragmentation is observed 90 min after detachment and is preceded by the sequential activation of preformed members of the CPP32 family of caspases. Activation of caspase 6 and cleavage of the endogenous caspase substrate poly(ADP-ribose) polymerase (EC 2.4.2.30 ) are detected within 15 min of detachment, 30–45 min before caspase 3 activation. Caspase 1 and caspase 10 are present as proenzymes, yet they remain inactive in response to this trigger of apoptosis. Human IEC are primed to rapidly undergo detachment-induced apoptosis involving the selective and sequential activation of preformed caspases. This study may enhance our understanding of physiological events occurring as IEC are shed. Their rapid apoptotic response to detachment may facilitate the high turnover of cells and ensure homeostasis in the intestinal epithelium.

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