scholarly journals An incoherent feedforward loop interprets NFκB/RelA dynamics to determine TNF-induced necroptosis decisions

2020 ◽  
Author(s):  
Marie Oliver Metzig ◽  
Ying Tang ◽  
Simon Mitchell ◽  
Brooks Taylor ◽  
Robert Foreman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cellular Response ◽  
Nuclear Factor Κb ◽  
Dual Roles ◽  
Feedforward Loop ◽  
Live Cell Microscopy ◽  
Death Kinetics ◽  
Cell Microscopy ◽  
Necrosis Factor

ABSTRACTBalancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor κB (NFκB), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro-inflammatory form of cell death. Whether TNF-induced NFκB cross-regulates TNF-induced necroptosis fate decisions is unclear. Live-cell microscopy and model-aided analysis of death kinetics identified a molecular circuit that interprets TNF-induced NFκB/RelA dynamics to control necroptosis decisions. Inducible expression of TNFAIP3/A20 forms an incoherent feedforward loop to interfere with the RIPK3-containing necrosome complex and protect a fraction of cells from transient, but not long-term TNF exposure. Furthermore, dysregulated NFκB dynamics often associated with disease diminish TNF-induced necroptosis. Our results suggest that TNF’s dual roles in either coordinating cellular responses to inflammation, or further amplifying inflammation are determined by a dynamic NFκB-A20-RIPK3 circuit, that could be targeted to treat inflammation and cancer.

Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α

2002 ◽  
Vol 282 (2) ◽  
pp. G257-G266 ◽  
Author(s):  
Hailing Liu ◽  
Brett E. Jones ◽  
Cynthia Bradham ◽  
Mark J. Czaja
Keyword(s):  
Cell Death ◽  
Oxidant Stress ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Tnf Α ◽  
Cyp2e1 Expression ◽  
Factor Α ◽  
Jnk Activation ◽  
Cytochrome P 450 ◽  
Necrosis Factor

The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-α (TNF-α)-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-α death. TNF-α treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-α response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-κB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-α-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-α stimulation. Sensitization to TNF-α-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-α toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-α toxicity in liver disease.

scholarly journals Proteome and Phosphoproteome Analysis in TNF Long Term-Exposed Primary Human Monocytes

2019 ◽  
Vol 20 (5) ◽  
pp. 1241 ◽  
Author(s):  
Bastian Welz ◽  
Rolf Bikker ◽  
Johannes Junemann ◽  
Martin Christmann ◽  
Konstantin Neumann ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Human Monocytes ◽  
Binding Motifs ◽  
Enhancer Binding Protein ◽  
Induced Signal ◽  
Necrosis Factor ◽  
Viral Oncogene Homolog

To better understand the inflammation-associated mechanisms modulating and terminating tumor necrosis factor (TNF-)induced signal transduction and the development of TNF tolerance, we analyzed both the proteome and the phosphoproteome in TNF long term-incubated (i.e., 48 h) primary human monocytes using liquid chromatography-mass spectrometry. Our analyses revealed the presence of a defined set of proteins characterized by reproducible changes in expression and phosphorylation patterns in long term TNF-treated samples. In total, 148 proteins and 569 phosphopeptides were significantly regulated (103 proteins increased, 45 proteins decreased; 377 peptides with increased and 192 peptides with decreased phosphorylation). A variety of these proteins are associated with the non-canonical nuclear factor κB (NF-κB) pathway (nuclear factor κB (NFKB) 2, v-rel reticuloendotheliosis viral oncogene homolog (REL) B, indolamin-2,3-dioxygenase (IDO), kynureninase (KYNU)) or involved in the negative regulation of the canonical NF-κB system. Within the phosphopeptides, binding motifs for specific kinases were identified. Glycogen synthase kinase (GSK) 3 proved to be a promising candidate, since it targets NF-κB inhibiting factors, such as CCAAT/enhancer binding protein (C/EBP) β. Our experiments demonstrate that both proteome and phosphoproteome analysis can be effectively applied to study protein/phosphorylation patterns of primary monocytes. These results provide new regulatory candidates and evidence for a complex network of specific but synergistically acting/cooperating mechanisms enabling the affected cells to resist sustained TNF exposure and resulting in the resolution of inflammation.

scholarly journals Mechanisms of liver disease: cross-talk between the NF-κB and JNK pathways

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Salvatore Papa ◽  
Concetta Bubici ◽  
Francesca Zazzeroni ◽  
Guido Franzoso
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Injury ◽  
Cellular Response ◽  
Protective Role ◽  
Activation Of Transcription ◽  
Tnf Α ◽  
Infected Cells ◽  
Hepatocyte Death ◽  
Necrosis Factor

Abstract The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated and virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury, specific intracellular processes are initiated to maintain liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes and activate different cellular response such as proliferation, survival and death. TNFα induces specific signaling pathways in hepatocytes that lead to activation of either pro-survival mediators or effectors of cell death. Whereas activation of transcription factor NF-κB promotes survival, c-Jun N-terminal kinases (JNKs) and caspases are strategic effectors of cell death in the TNFα-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity and suggests that NF-κB plays a protective role against JNK-induced hepatocyte death. Identification of the mechanisms regulating interplay between the NF-κB and JNK pathways is required in the search for novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.

scholarly journals Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-κB Activity-Augmenting Tumor Necrosis Factor-α–Mediated T-Cell Death: Protection by Curcumin

2007 ◽  
Vol 67 (1) ◽  
pp. 362-370 ◽  
Author(s):  
Sankar Bhattacharyya ◽  
Debaprasad Mandal ◽  
Gouri Sankar Sen ◽  
Suman Pal ◽  
Shuvomoy Banerjee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals TWEAKing death

2008 ◽  
Vol 182 (1) ◽  
pp. 15-17 ◽  
Author(s):  
Jonathan D. Ashwell
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Nuclear Factor Κb ◽  
Tnf Receptor ◽  
Tumor Cell Death ◽  
Cell Death Pathways ◽  
Tnf Α ◽  
Selective Elimination ◽  
Smac Mimetics ◽  
Necrosis Factor

Smac mimetics (inhibitor of apoptosis [IAP] antagonists) are synthetic reagents that kill susceptible tumor cells by inducing degradation of cellular IAP (cIAP) 1 and cIAP2, nuclear factor κB activation, tumor necrosis factor (TNF) α production, TNF receptor 1 occupancy, and caspase-8 activation. In this issue of The Journal of Cell Biology, Vince et al. (see p. 171) report remarkable similarities in the events leading to tumor cell death triggered by the cytokine TWEAK (TNF-like weak inducer of apoptosis) and IAP antagonists. Although the mechanistic details differ, a common and necessary feature that is also shared by TNF receptor 2 signaling is reduction in the level of cIAP1 and, in some cases, cIAP2 and TNF receptor-associated factor 2. These findings not only extend our appreciation of how cell death pathways are kept in check in tumors, they reinforce the possible utility of induced cIDE (cIAP deficiency) in the selective elimination of neoplastic cells.

scholarly journals Inhibition of EZH2 (Enhancer of Zeste Homolog 2) Attenuates Neuroinflammation via H3k27me3/SOCS3/TRAF6/NF-κB (Trimethylation of Histone 3 Lysine 27/Suppressor of Cytokine Signaling 3/Tumor Necrosis Factor Receptor Family 6/Nuclear Factor-κB) in a Rat Model of Subarachnoid Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3320-3331 ◽  
Author(s):  
Yujie Luo ◽  
Yuanjian Fang ◽  
Ruiqing Kang ◽  
Cameron Lenahan ◽  
Marcin Gamdzyk ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuroprotective Effect ◽  
Tumor Necrosis Factor Receptor ◽  
Early Brain Injury ◽  
Nuclear Factor Κb ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Histone 3 ◽  
Necrosis Factor

Background and Purpose: Neuroinflammation has been proven to play an important role in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). EZH2 (enhancer of zeste homolog 2)-mediated H3K27Me3 (trimethylation of histone 3 lysine 27) has been recognized to play a critical role in multiple inflammatory diseases. However, there is still a lack of evidence to address the effect of EZH2 on the immune response of SAH. Therefore, the aim of this study was to determine the role of EZH2 in SAH-induced neuroinflammation and explore the effect of EZH2 inhibition with its specific inhibitor EPZ6438. Methods: The endovascular perforation method was performed on rats to induce subarachnoid hemorrhage. EPZ6438, a specific EZH2 inhibitor, was administered intraperitoneally at 1 hour after SAH. SOCS3 (Suppressor of cytokine signaling 3) siRNA and H3K27me3 CRISPR were administered intracerebroventricularly at 48 hours before SAH to explore potential mechanisms. The SAH grade, short-term and long-term neurobehavioral tests, immunofluorescence staining, and western blots were performed after SAH. Results: The expression of EZH2 and H3K27me3 peaked at 24 hours after SAH. In addition, inhibition of EZH2 with EPZ6438 significantly improved neurological deficits both in short-term and long-term outcome studies. Moreover, EPZ6438 treatment significantly decreased the levels of EZH2, H3K27Me3, pathway-related proteins TRAF6 (TNF [tumor necrosis factor] receptor family 6), NF-κB (nuclear factor-κB) p65, proinflammatory cytokines TNF-α, IL (interleukin)-6, IL-1β, but increased the expression levels of SOCS3 and anti-inflammatory cytokine IL-10. Furthermore, administration of SOCS3 siRNA and H3k27me3-activating CRISPR partly abolished the neuroprotective effect of EPZ6438, which indicated that the neuroprotective effect of EPZ6438 acted, at least partly, through activation of SOCS3. Conclusions: In summary, the inhibition of EZH2 by EPZ6438 attenuated neuroinflammation via H3K27me3/SOCS3/TRAF6/NF-κB signaling pathway after SAH in rats. By targeting EZH2, this study may provide an innovative method to ameliorate early brain injury after SAH.

A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2376-2384 ◽  
Author(s):  
Soizic Daniel ◽  
Maria B. Arvelo ◽  
Virendra I. Patel ◽  
Christopher R. Longo ◽  
Gautam Shrikhande ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Killer Cell ◽  
Nuclear Factor Κb ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Cell Death Pathways ◽  
Executioner Caspases ◽  
First Time ◽  
Necrosis Factor

Abstract A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)–mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor–κB (NF-κB). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell–mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders.

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