Redox Regulation of Apoptosis by Members of the TNF Superfamily (original) (raw)
Related papers
Cancer Letters, 2002
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as an extracellular signal triggering apoptosis in tumor cells. However, the molecular mechanisms leading to the apoptosis are largely unknown. To characterize the molecular events involved in TRAIL-induced apoptosis, we examined the association of reactive oxygen species (ROS) in human adenocarcinoma HeLa cells. In this study, we show strong ROS accumulation upon TRAIL induction, with activation of caspases, followed by apoptosis. The pre-treatment with g-glutamylcysteinylglycine or estrogen, both effective antioxidants, significantly attenuated TRAIL-induced apoptosis through the reduction of ROS accumulation and diminished caspases activity. Furthermore, zVAD-fmk, an inhibitor of pan-caspase, effectively inhibited the activation of caspases and prevented apoptosis by TRAIL, although TRAIL-induced ROS generation was not attenuated. These data indicate that ROS may play a role as an upstream mediator of caspases. Taken together, our results suggest that oxidative stress mediates TRAIL-induced apoptosis in HeLa cells.
TNF-Induced Signaling in Apoptosis
1999
Out of the almost 17 members of the TNF superfamily, TNF is probably the most potent inducer of apoptosis. TNF activates both cell-survival and cell-death mechanisms simultaneously. Activation of NF-kB-dependent genes regulates the survival and proliferative effects pf TNF, whereas activation of caspases regulates the apoptotic effects. TNF-induced apoptosis is mediated primarily through the activation of type I receptors, the death domain of which recruits more than a dozen different signaling proteins, which together are considered part of an apoptotic cascade. This cascade does not, however, account for the role of reactive oxygen intermediates, ceramide, phospholipases, and serine proteases which are also inplicated in TNF-induced apoptosis. This cascade also does not explain how type II TNF receptors which lack the death domain, induce apoptosis. Nevertheless, this review of apoptosis signaling will be limited to those proteins that makeup the cascade.
The American Journal of Pathology, 2000
Tumor necrosis factor (TNF) is a mediator of the acute phase response in the liver and can initiate proliferation and cause cell death in hepatocytes. We investigated the mechanisms by which TNF causes apoptosis in hepatocytes focusing on the role of oxidative stress, antioxidant defenses, and mitochondrial damage. The studies were conducted in cultured AML12 cells, a line of differentiated murine hepatocytes. As is the case for hepatocytes in vivo, AML12 cells were not sensitive to cell death by TNF alone, but died by apoptosis when exposed to TNF and a small dose of actinomycin D (Act D). Morphological signs of apoptosis were not detected until 6 hours after the treatment and by 18 hours ϳ50% of the cells had died. Exposure of the cells to TNF؉Act D did not block NFB nuclear translocation, DNA binding, or its overall transactivation capacity. Induction of apoptosis was characterized by oxidative stress indicated by the loss of NAD(P)H and glutathione followed by mitochondrial damage that included loss of mitochondrial membrane potential, inner membrane structural damage, and mitochondrial condensation. These changes coincided with cytochrome C release and the activation of caspases-8, -9, and -3. TNF-induced apoptosis was dependent on glutathione levels. In cells with decreased levels of glutathione, TNF by itself in the absence of transcriptional blocking acted as an apoptotic agent. Conversely, the antioxidant ␣-lipoic acid, that protected against the loss of glutathione in cells exposed to TNF؉Act D completely prevented mitochondrial damage, caspase activation, cytochrome C release, and apoptosis. The results demonstrate that apoptosis induced by TNF؉Act D in AML12 cells involves oxidative injury and mitochondrial damage. As injury was regulated to a larger extent by the glutathione content of the cells, we suggest that the combination of TNF؉Act D causes apoptosis be-cause Act D blocks the transcription of genes required for antioxidant defenses.
TNF-α activates at least two apoptotic signaling cascades
Oncogene, 1998
Apoptosis, the process whereby cells activate an intrinsic death program, can be induced in HeLa cells by TNF-a treatment. The aims of the present study were (i) to examine the precise role and the origin of Reactive Oxygen Species (ROS) in the TNF-a-induced programmed cell death, (ii) to characterize and order the morphological and mitochondrial changes associated with this process and (iii) to link these events with the activation of caspases. Analyses were performed on TNF-a-treated cells in the presence of an anti-oxidant, or of a general caspase inhibitor. To assess the role of mitochondria in the cell death signal transduction, these studies were also realized on HeLa-variant cell lines lacking functional mitochondrial respiratory chain. We show that at least two separate signaling cascades, both mediated by Z-VAD-sensitive caspase(s), contribute to the TNF-a-induced apoptosis of HeLa cells. One signaling pathway involves an early mitochondriadependent ROS production, the other being ROSindependent.
Activation of apoptosis signalling pathways by reactive oxygen species
Biochimica et biophysica acta. Molecular cell research, 2016
Reactive oxygen species (ROS) are short-lived and highly reactive molecules. The generation of ROS in cells exists in equilibrium with a variety of antioxidant defences. At low to modest doses, ROS are considered to be essential for regulation of normal physiological functions involved in development such as cell cycle progression and proliferation, differentiation, migration and cell death. ROS also play an important role in the immune system, maintenance of the redox balance and have been implicated in activation of various cellular signalling pathways. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. Apoptosis is a highly regulated process that is essential for the development and survival of multicellular organisms. These organisms often need to discard cells that are superfluous or potentially harmful, having accumulated mutations or become infected by pathogens. Apoptosis features a characteristic set of morphological and biochemical features whereby cells undergo a cascade of self-destruction. Thus, proper regulation of apoptosis is essential for maintaining normal cellular homeostasis. ROS play a central role in cell signalling as well as in regulation of the main pathways of apoptosis mediated by mitochondria, death receptors and the endoplasmic reticulum (ER). This review focuses on current understanding of the role of ROS in each of these three main pathways of apoptosis. The role of ROS in the complex interplay and crosstalk between these different signalling pathways remains to be further unravelled during the coming years.
Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage
Biochemistry (Moscow), 2014
Vascular endothelium performs numerous functions: it controls the blood clotting system, vascular tone, tissue perfusion, exchange of fluid and macromolecules between the blood and tissues, and immune system development and immune response [1]. Therefore, any damage or excessive activation of the endothelium leads to serious pathologies [2]. Various stimuli considered as cardiovascular risk factors (e.g. tumor necrosis factor alpha (TNFα)) cause apoptosis of endothelial cells in vitro [3]. Moreover, apoptosis of endothelial cells was observed in vivo in humans and other animals with various pathologies and in old animals [3, 4]. One of the significant risk factors for endothelial dysfunction is the increase in circulatory inflammatory cytokines, particularly TNFα [5]. TNFα binding to its receptors on the cell surface triggers a series of complex signaling cascades [6, 7] leading to different effects depending on the conditions and type of cell. In endothelial cells, TNFα activates secretion of blood coagulation factors, NO-synthase, expression of tissue factors, adhesion molecules, inflammatory cytokines and chemokines, transendothelial vesicular transport, cytoskeleton reorganization, disassembly of cell-cell contacts, and cell death [5]. TNFα can initiate endothelial cell apoptosis either due to direct activation of caspase cascades [8] or due to release of mitochondrial proapoptotic proteins (cytochrome c, AIF, DIABLO, etc.) [9].
Role of reactive oxygen species (ROS) in apoptosis induction
Apoptosis, 2000
Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.
Redox Regulation of Tumor Necrosis Factor Signaling
Antioxidants & Redox Signaling, 2009
Tumor necrosis factor-a (TNF) is a key cytokine that has been shown to play important physiologic (e.g., inflammation) and pathophysiologic (e.g., various liver pathologies) roles. In liver and other tissues, TNF treatment results in the simultaneous activation of an apoptotic pathway (i.e., TRADD, RIP, JNK) and a survival pathway mediated by NF-kB transcription of survival genes (i.e., GADD45b, Mn-SOD, cFLIP). The cellular response (e.g., proliferation versus apoptosis) to TNF is determined by the balance between the apoptotic signaling pathway and the NF-kB survival pathway stimulated by TNF. Reactive oxygen species (ROS) are important modulators of signaling pathways and can regulate both apoptotic signaling and NF-kB transcription triggered by TNF. ROS are important in mediating the sustained activation of JNK, to help mediate apoptosis after TNF treatment. In some cells, ROS are second messengers that mediate apoptosis after TNF stimulation. Conversely, ROS can cause redox modifications that inhibit NF-kB activation, which can lead to cell death triggered by TNF. Consequently, the redox status of cells can determine the biologic response that TNF will induce in cells. In many liver pathologies, ROS generated extrinsically (e.g., inflammation) or intrinsically (i.e., drugs, toxins) may act in concert with TNF to promote hepatocyte death and liver injury through redox inhibition of NF-kB. Antioxid. Redox Signal. 11, 2245-2263.