Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65

Takada, Yasunari; Mukhopadhyay, Asok; Kundu, Gopal C.; Mahabeleshwar, Ganapati H.; Singh, Sujay; Aggarwal, Bharat B.

doi:10.1074/jbc.m212389200

Cited by 495NF-κB Signaling PathwaysRedox biology and oxidative stressImmune Response and Inflammation

Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65

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Takada, Yasunari, Mukhopadhyay, Asok, Kundu, Gopal C., Mahabeleshwar, Ganapati H., Singh, Sujay, Aggarwal, Bharat B.·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m212389200

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Abstract

Although it is well established that reactive oxygen intermediates mediate the NF-kappaB activation induced by most agents, how H2O2 activates this transcription factor is not well understood. We found that treatment of human myeloid KBM-5 cells with H2O2 activated NF-kappaB in a dose- and time-dependent manner much as tumor necrosis factor (TNF) did but unlike TNF, H2O2 had no effect on IkappaBalpha degradation. Unexpectedly, however, like TNF-induced activation, H2O2-induced NF-kappaB activation was blocked by the calpain inhibitor N-Ac-Leu-Leu-norleucinal, suggesting that a proteosomal pathway was involved. Although H2O2 activated IkappaBalpha kinase, it did not induce the serine phosphorylation of IkappaBalpha. Like TNF, H2O2 induced the serine phosphorylation of the p65 subunit of NF-kappaB, leading to its nuclear translocation. We found that H2O2 induced the tyrosine phosphorylation of IkappaBalpha, which is needed for NF-kappaB activation. We present several lines of evidence to suggest that the Syk protein-tyrosine kinase is involved in H2O2-induced NF-kappaB activation. First, H2O2 activated Syk in KBM-5 cells; second, H2O2 failed to activate NF-kappaB in cells that do not express Syk protein; third, overexpression of Syk increased H2O2-induced NF-kappaB activation; and fourth, reduction of Syk transcription using small interfering RNA inhibited H2O2-induced NF-kappaB activation. We also showed that Syk induced the tyrosine phosphorylation of IkappaBalpha, which caused the dissociation, phosphorylation, and nuclear translocation of p65. Thus, overall, our results demonstrate that H2O2 induces NF-kappaB activation, not through serine phosphorylation or degradation of IkappaBalpha, but through Syk-mediated tyrosine phosphorylation of IkappaBalpha

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H2O2-mediated NFκB activation does not involve degradation of IκB.
“However, this process does not involve the degradation of IκB, which is controlled by IκB kinase (IKK)-mediated serine phosphorylation.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [144]
H2O2-mediated NFκB activation is regulated by activation of spleen tyrosine kinase (Syk).
“H2O2-mediated activation is, instead, regulated by activation of spleen tyrosine kinase (Syk) [144].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [144]
H2O2-mediated NFκB activation results from phosphorylation of IκB tyrosine residues.
“Multiple studies have shown that H2O2-mediated NFκB activation results from phosphorylation of IκB tyrosine residues [143,144].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [144]
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 [144]

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Authors: Takada, Y., Mukhopadhyay, A., Kundu, G. C., Mahabeleshwar, G. H., Singh, S., & Aggarwal, B. B.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
National Centre for Cell Science (IN)
Corresponding author: Aggarwal, Bharat B.
ORCID: Mukhopadhyay, Asok
Kundu, Gopal C.
Mahabeleshwar, Ganapati H.
Singh, Sujay
Aggarwal, Bharat B.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-06
Volume: 278
Issue: 26
Pages: 24233-24241
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m212389200
OpenAlex: W1974559428
Cited by: 495
References: 52
Citations by year: 2026: 18 · 2025: 11 · 2024: 26 · 2023: 18 · 2022: 27 · 2021: 31 · 2020: 27 · 2019: 20 · 2018: 18 · 2017: 21 · 2016: 25 · 2015: 15 · 2014: 10 · 2013: 22 · 2012: 17
FWCI: 11.03
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6340 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: U.S. Department of Defense
National Institute of Immunology
National Institutes of Health (1r43gm068358-01)
U.S. Army
National Cancer Institute (P01 CA-91844, P01CA091844)
National Institute of General Medical Sciences (R43 GM68358-01)
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 › Immune Response and Inflammation
Keywords: hydrogen peroxide, NF-κB activation, calpain, proteasomal degradation, IκBα kinase, nuclear translocation, reactive oxygen species
MeSH terms: Syk Kinase, Dose-Response Relationship, Drug, Enzyme Precursors, Humans, Hydrogen Peroxide, Kinetics, Phosphorylation, Protein-Tyrosine Kinases, Serine, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tyrosine, NF-kappa B, I-kappa B Proteins, Active Transport, Cell Nucleus, Intracellular Signaling Peptides and Proteins, Transcription Factor RelA

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Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65

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