IκB is a sensitive target for oxidation by cell-permeable chloramines: inhibition of NF-κB activity by glycine chloramine through methionine oxidation
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Hypochlorous acid (HOCl) is produced by the neutrophil enzyme, myeloperoxidase, and reacts with amines to generate chloramines. These oxidants react readily with thiols and methionine and can affect cell-regulatory pathways. In the present study, we have investigated the ability of HOCl, glycine chloramine (Gly-Cl) and taurine chloramine (Tau-Cl) to oxidize IkappaBalpha, the inhibitor of NF-kappaB (nuclear factor kappaB), and to prevent activation of the NF-kappaB pathway in Jurkat cells. Glycine chloramine (Gly-Cl) and HOCl were permeable to the cells as determined by oxidation of intracellular GSH and inactivation of glyceraldehyde-3-phosphate dehydrogenase, whereas Tau-Cl showed no detectable cell permeability. Both Gly-Cl (20-200 muM) and HOCl (50 microM) caused oxidation of IkappaBalpha methionine, measured by a shift in electrophoretic mobility, when added to the cells in Hanks buffer. In contrast, a high concentration of Tau-Cl (1 mM) in Hanks buffer had no effect. However, Tau-Cl in full medium did modify IkappaBalpha. This we attribute to chlorine exchange with other amines in the medium to form more permeable chloramines. Oxidation by Gly-Cl prevented IkappaBalpha degradation in cells treated with TNFalpha (tumour necrosis factor alpha) and inhibited nuclear translocation of NF-kappaB. IkappaBalpha modification was reversed by methionine sulphoxide reductase, with both A and B forms required for complete reduction. Oxidized IkappaBalpha persisted intracellularly for up to 6 h. Reversion occurred in the presence of cycloheximide, but was prevented if thioredoxin reductase was inhibited, suggesting that it was due to endogenous methionine sulphoxide reductase activity. These results show that cell-permeable chloramines, either directly or when formed in medium, could regulate NF-kappaB activation via reversible IkappaBalpha oxidation.
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N-chlorotaurine formation may cause negative regulation of inflammatory processes by multiple distinct molecular mechanisms attenuating NF-kB and related cytokine signaling.
“Importantly, N-chlorotaurine formation may cause the negative regulation of inflammatory processes by multiple distinct molecular mechanisms attenuating NF-kB and related cytokine signaling (88, 116).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [116]
Negative modulation of NF-κB by N-chlorotaurine and other chloramines such as glycine chloramine is thought to originate from oxidation of Met45 in IκB, preventing its ubiquitination and proteasomal degradation.
“Negative modulation of NF-κB by N-chlorotaurine (and other chloramines such as glycine chloramine) is thought to originate from oxidation of Met45 in IκB (preventing its ubiquitination and proteasomal degradation) (116, 117).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [116]
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- Authors
- Midwinter, R. G., Cheah, F.-C., Moskovitz, J., Vissers, M. C., & Winterbourn, C. C.
- Affiliations
- Free Radical Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand
- University of Kansas (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2006-04-26
- Volume
- 396
- Issue
- 1
- Pages
- 71-78
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2116161116
- Cited by
- 85
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 4 · 2022: 7 · 2021: 8 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 6
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Otago
- Health Research Council of New Zealand
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- IκBα, NF-κB activation, taurine chloramine, hypochlorous acid, methionine oxidation, methionine sulfoxide reductase, thioredoxin reductase, membrane permeability, TNF-α, nuclear translocation, myeloperoxidase, Jurkat cells, methionine sulfoxide
- MeSH terms
- NF-KappaB Inhibitor alpha, Antioxidants, Cell Membrane Permeability, Chloramines, Glutathione, Glycine, Humans, Hypochlorous Acid, Methionine, Neoplasm Proteins, Neutrophils, Oxidation-Reduction, Taurine, Tumor Necrosis Factor-alpha, NF-kappa B, Oxidants, Jurkat Cells, I-kappa B Proteins, Active Transport, Cell Nucleus
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