NF‐κB inhibits TNF‐induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death
Open accessAbstract
NF-kappaB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-kappaB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-kappaB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death
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Cells without intact NF-κB lack SOD2 induction and accumulate ROS at much higher levels than wild-type cells when treated with TNFα, corresponding with increased JNK activation.
“Cells without intact NF-κB lack SOD2 induction and accumulate ROS at much higher levels than their wild-type counterparts when treated with TNFα, corresponding with increased JNK activation 53, 60.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [60]
Treatment of cells with antioxidants inhibits TNFα-induced killing of NF-κB-deficient cells.
“Furthermore, treatment of cells with antioxidants inhibits TNFα-induced killing of NF-κB-deficient cells 60, 64.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [60]
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- Authors
- Sakon, S., Xue, X., Takekawa, M., Sasazuki, T., Okazaki, T., Kojima, Y., Piao, J., Yagita, H., Okumura, K., Doi, T., & Nakano, H.
- Affiliations
- Juntendo University (JP)
- Japan Science and Technology Agency (JP)
- RIKEN BioResource Research Center (JP)
- Corresponding author
- Nakano, Hiroyasu
- Venue
- The EMBO Journal
- Published
- 2003-08-01
- Volume
- 22
- Issue
- 15
- Pages
- 3898-3909
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC169052
- OpenAlex
- W2170236911
- Cited by
- 497
- References
- 43
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 10 · 2019: 13 · 2018: 12 · 2017: 17 · 2016: 24 · 2015: 22 · 2014: 22 · 2013: 33 · 2012: 30
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NF-κB, TNF-α, reactive oxygen species, MAPK activation, c-Jun N-terminal kinase, necrosis, apoptosis, TRAF2, TRAF5, NF-κB p65, antioxidants, murine embryonic fibroblasts, oxidative stress
- MeSH terms
- Animals, Glutathione, Microscopy, Electron, NADP, Tumor Necrosis Factor-alpha, NF-kappa B, Cell Death, Reactive Oxygen Species, Mitogen-Activated Protein Kinases, Mice
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