Nuclear Factor kB-independent Cytoprotective Pathways Originating at Tumor Necrosis Factor Receptor-associated Factor 2

Natoli, Gioacchino; Costanzo, Antonio; Guido, Francesco; Moretti, Francesca; Bernardo, Antonietta; Burgio, Vito L.; Agresti, Cristina; Levrero, Massimo

doi:10.1074/jbc.273.47.31262

Cited by 91 publications

(81 citation statements)

References 67 publications

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“…The differential effect of the TRAF6-C construct in response to LPS and TNF suggests that TRAF6 signaling in endothelial cells is stimulus dependent. TRAF2-C has previously been shown to sensitize other cell types to TNF-induced death (39). As a further control, we initiated apoptosis of HMEC-TRAF6-C, HMEC-TRAF2-C, and vector-transduced HMEC with different doses of ceramide (0 -50 M).…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Hull

McLean

Wong

et al. 2002

The Journal of Immunology

101

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Inflammatory mediators such as TNF and bacterial LPS do not cause significant apoptosis of endothelial cells unless the expression of cytoprotective genes is blocked. In the case of TNF, the transcription factor NF-κB conveys an important survival signal. In contrast, even though LPS can also activate NF-κB, this signal is dispensable for LPS-inducible cytoprotective activity. LPS intracellular signals are transmitted through a member of the Toll-like receptor family, TLR4. This family of receptors transduces signals through a downstream molecule, TNFR-associated factor 6 (TRAF6). In this study, we demonstrate that the C-terminal fragment of TRAF6 (TRAF6-C) inhibits LPS-induced NF-κB nuclear translocation and c-Jun NH2-terminal kinase (JNK) activation in endothelial cells. In contrast, LPS activation of p38 kinase is not inhibited by TRAF6-C. TRAF6-C also inhibits LPS-initiated endothelial apoptosis, but potentiates TNF-induced apoptosis. LPS-induced loss of mitochondrial transmembrane potential, cytochrome c release, and caspase activation are all blocked by TRAF6-C. We demonstrate that TRAF6 signals apoptosis via JNK activation, since inhibition of JNK activation using a dominant-negative mutant also inhibits apoptosis. JNK inhibition blocks caspase activation, but the reverse is not true. Hence, JNK activation lies upstream of caspase activation in response to LPS stimulation.

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Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Hull

McLean

Wong

et al. 2002

The Journal of Immunology

101

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“…Several studies indicate that NF-B activation blocks apoptosis, while others show that NF-B activation has no effect on TNFinduced apoptosis (63)(64)(65)(66), and then there are reports indicating that NF-B activation is required for apoptosis (67,68). The inhibition of NF-B by vesnarinone did not potentiate the apoptotic effects of TNF but, rather, suppressed it, suggesting that either inhibition of apoptosis by vesnarinone is dependent on inhibition of NF-B activation or that NF-B and apoptosis are inhibited independently of each other.…”

Section: Discussionmentioning

confidence: 99%

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Manna

Aggarwal

2000

The Journal of Immunology

161

180

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Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-κB in these responses, we hypothesized that vesnarinone must modulate NF-κB activation. We investigated the effect of vesnarinone on NF-κB activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-κB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-κB activation in a variety of cells. NF-κB-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-κB activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-κB-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-κB-inducing kinase sites by vesnarinone, thus suppressing NF-κB reporter gene expression. Vesnarinone also blocked NF-κB activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-κB and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone’s ability to suppress inflammation, immunomodulation, and growth regulation.

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“…The NF-κB activation that is induced by the over-expression of TRAF2 was found to be insufficient to protect cells from apoptosis that is induced by TNF and cycloheximide together. This indicates an essential role for additional components in the cytoprotective response (Natoli et al, 1998).…”

Section: How Nf-κb Suppresses Apoptosismentioning

confidence: 99%

Nuclear Factor-κB Activation: A Question of Life or Death

Shishodia¹,

Aggarwal²

2002

BMB Reports

206

168

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Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-κB activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-κB and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which may or may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-κB controls apoptosis.

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Nuclear Factor kB-independent Cytoprotective Pathways Originating at Tumor Necrosis Factor Receptor-associated Factor 2

Cited by 91 publications

References 67 publications

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Nuclear Factor-κB Activation: A Question of Life or Death

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