Inhibition of Fas-Induced Apoptotic Cell Death by Osmotic Cell Shrinkage

Gulbins, Erich; Welsch, Julia; Lepple-Wienhuis, A.; Heinle, H.; Läng, Florian

doi:10.1006/bbrc.1997.6775

Cited by 35 publications

(24 citation statements)

References 27 publications

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“…Within lysosomes the cell responds to the toxin with an activation of the acid sphingomyelinase, formation of ceramides, the release of cathepsins, an activation of the inflammasome and the release of pro-inflammatory cytokines. The toxin may generate reactive oxygen species within the lysosome that have been previously shown to stimulate the enzyme activity of the acid sphingomyelinase [39, 44-48]. Alternatively, activation of the acid sphingomyelinase by α-toxin might be mediated by a direct contact of the acid sphingomyelinase with α-toxin and a conformational change of the acid sphingomyelinase [48].…”

Section: Discussionmentioning

confidence: 99%

“…The toxin may generate reactive oxygen species within the lysosome that have been previously shown to stimulate the enzyme activity of the acid sphingomyelinase [39, 44-48]. Alternatively, activation of the acid sphingomyelinase by α-toxin might be mediated by a direct contact of the acid sphingomyelinase with α-toxin and a conformational change of the acid sphingomyelinase [48]. In addition, the toxin may activate proteases that induce a limited cleavage and thereby activation of the acid sphingomyelinase, similar to the activation of the acid sphingomyelinase by caspases in multivesicular bodies [49].…”

Section: Discussionmentioning

confidence: 99%

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Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Gulbins

Edwards

et al. 2017

Cell Physiol Biochem

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Background/Aims: Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Gulbins

Edwards

et al. 2017

Cell Physiol Biochem

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“…Expectedly, the inhibitor does not modify the Na ROS production is instrumental in the killing of pathogens and thus an important element in the innate immune response [9]. Owing to the pH sensitivity of ROS production [12,13] Cell volume has previously been shown to influence both, formation of ROS and antioxidative defence [45][46][47][48]. Cell shrinkage has been shown to interfere with generation of ROS and the increase in cell volume following exposure to LPS may thus support the formation of ROS.…”

Section: Discussionmentioning

confidence: 99%

Effect of Bacterial Lipopolysaccharide on Na<sup>+</sup>/H<sup>+</sup> Exchanger Activity in Dendritic Cells

Rotte¹,

Pasham²,

Eichenmüller³

et al. 2010

Cell Physiol Biochem

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“…The apoptosis induced by hypertonicity exhibits a partial requirement for intact RNA transcription and protein translation, and is partially inhibited by chelation of intracellular calcium and by inhibition of tyrosine kinase activity. Several additional signaling pathways, including the Fas pathway, 35 and a growing number of mitochondrial proteins, have been implicated in the apoptotic process in nonendothelial cell types. Future studies will examine their possible involvement in endothelial cell apoptosis induced by hypertonicity.…”

Section: Discussionmentioning

confidence: 99%

Mannitol at Clinical Concentrations Activates Multiple Signaling Pathways and Induces Apoptosis in Endothelial Cells

Malek¹,

Goss²,

Jiang³

et al. 1998

Stroke

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Background and Purpose-Hyperosmotic mannitol therapy is widely used in the clinical setting for acute and subacute reduction in brain edema, to decrease muscle damage in compartment syndrome, and to improve renal perfusion. Though beneficial rheological effects commonly are attributed to mannitol, its direct effects on endothelial cells are poorly understood. Methods-We studied the effect of hypertonic and hypotonic stress on bovine aortic endothelial (BAE) cells, using mannitol, urea, and sodium chloride and medium dilution in vitro. Results-Exposure to incremental osmolar concentrations of 300 mOsm of each osmotic agent increased apoptosis in BAE cells (mannitolХNaClϾurea). Induced programmed cell death was detected by DAPI staining of intact cell nuclei, and by TUNEL and DNA fragmentation ladder assays. Mannitol-induced apoptosis exhibited dose dependence (42% of cells at 300 mOsm [PϽ0.0001] compared with 1.2% of control cells) and was also observed in bovine smooth muscle cells. Mannitol-induced apoptosis was attenuated Ϸ50% in the presence of cycloheximide or actinomycin D. Hypertonic mannitol and NaCl, but not urea, increased tyrosine phosphorylation of the focal adhesion contact-associated proteins paxillin and FAK. Hypotonic medium, which did not lead to apoptosis, increased protein tyrosine phosphorylation of FAK but not of paxillin. Addition of mannitol or NaCl also produced sustained increases in c-Jun NH2-terminal kinase (JNK) activity. In addition, hypertonic mannitol increased intracellular free [Ca 2ϩ ] in a dose-dependent manner. Chelation of intracellular Ca 2ϩ with quin2-AM (10 mol/L) inhibited mannitol-induced apoptosis Ϸ50%, as to a lesser extent did inhibition of tyrosine kinase activity with herbimycin (1 mol/L). Conclusions-We have shown that hypertonic mannitol exposure induces endothelial cell apoptosis, accompanied by activation of tyrosine and stress kinases, phosphorylation of FAK and paxillin, and elevation of intracellular free [Ca 2ϩ ]. The apoptosis is attenuated by inhibition of transcription or translation, by inhibition of tyrosine kinases, or by intracellular Ca 2ϩ buffering. These data suggest that clinical use of the osmotic diuretic mannitol may exert direct deleterious effects on vascular endothelium. (Stroke. 1998;29:2631-2640.)

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Inhibition of Fas-Induced Apoptotic Cell Death by Osmotic Cell Shrinkage

Cited by 35 publications

References 27 publications

Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides

Effect of Bacterial Lipopolysaccharide on Na<sup>+</sup>/H<sup>+</sup> Exchanger Activity in Dendritic Cells

Mannitol at Clinical Concentrations Activates Multiple Signaling Pathways and Induces Apoptosis in Endothelial Cells

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