Interleukin-1β Induction of NFκB Is Partially Regulated by H2O2-mediated Activation of NFκB-inducing Kinase
Open accessAbstract
Reactive oxygen species (ROS) have been demonstrated to act as second messengers in a number of signal transduction pathways, including NFkappaB. However, the mechanism(s) by which ROS regulate NFkappaB remain unclear and controversial. In the present report, we describe a mechanism whereby interleukin-1beta (IL-1beta) stimulation of NFkappaB is partially regulated by H2O2-mediated activation of NIK and subsequent NIK-mediated phosphorylation of IKKalpha. IL-1beta induced H2O2 production in MCF-7 cells and clearance of this ROS through the expression of GPx-1 reduced NFkappaB transcriptional activation by inhibiting NIK-mediated phosphorylation of IKKalpha. Although IKKalpha and IKKbeta were both involved in IL-1beta-mediated activation of NFkappaB, only the IKKalpha-dependent component was modulated by changes in H2O2 levels. Interestingly, in vitro reconstitution experiments demonstrated that NIK was activated by a very narrow range of H2O2 (1-10 microM), whereas higher concentrations (100 microM to 1 mM) inhibited NIK activity. Treatment of cells with the general Ser/Thr phosphatase inhibitor (okadaic acid) lead to activation of NFkappaB and enhanced NIK activity as a IKKalpha kinase, suggesting that ROS may directly regulate NIK through the inhibition of phosphatases. Recruitment of NIK to TRAF6 following IL-1beta stimulation was inhibited by H2O2 clearance and Rac1 siRNA, suggesting that Rac-dependent NADPH oxidase may be a source of ROS required for NIK activation. In summary, our studies have demonstrated that redox regulation of NIK by H2O2 is mechanistically important in IL-1beta induction of NFkappaB activation.
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Exogenous H2O2 or induction of H2O2 release by IL1β or LPS can activate NFκB in multiple cell types, including human myeloid KBM-5 cells, human epithelial-like MCF-7 cells, mouse EL-5 T-cells and macrophages.
“Exogenous application of H2O2 or induction of H2O2 release by IL1β or LPS treatment can activate NFκB in multiple cell types, including human myeloid KBM-5 cells, human epithelial-like MCF-7 cells, mouse EL-5 T-cells and macrophages [143,144,145,146].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [145]
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- Authors
- Li, Q., & Engelhardt, J. F.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Engelhardt, John F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 281
- Issue
- 3
- Pages
- 1495-1505
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2083331590
- Cited by
- 219
- References
- 67
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 12 · 2021: 12 · 2020: 19 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 14 · 2015: 7 · 2014: 11 · 2013: 10 · 2012: 12
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK54759)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54759, P30 DK 54759, R01DK067928, P30DK054759)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- IL-1β, NF-κB activation, NIK, hydrogen peroxide, reactive oxygen species, redox regulation, glutathione peroxidase 1, TRAF6, Rac1, NADPH oxidase, MCF-7 cells, phosphatase inhibition
- MeSH terms
- NF-kappaB-Inducing Kinase, Breast Neoplasms, Enzyme Activation, Female, Genetic Vectors, Glutathione Peroxidase, Humans, Hydrogen Peroxide, Interleukin-1, Phosphorylation, Transcription, Genetic, NF-kappa B, Protein Serine-Threonine Kinases, Genes, Reporter, Cell Line, Tumor
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