Cited by 273NF-κB Signaling PathwaysAntioxidant Activity and Oxidative StressNatural Compounds in Disease Treatment

The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: Role of H2O2 in NF-κB activation

Kim, Ji-Hee, Na, Hee-Jun, Kim, Chun-Ki, Kim, Ji-Yoon, Ha, Kwon-Soo, Lee, Hansoo, Chung, Hun-Taeg, Kwon, Ho Jeong +2 more·2008·Free Radical Biology and Medicine

Abstract

Reactive oxygen species (ROS) have been implicated in the regulation of NF-kappaB activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-kappaB activation remain poorly defined. We found that the non-provitamin A carotenoid, lutein, decreased intracellular H(2)O(2) accumulation by scavenging superoxide and H(2)O(2) and the NF-kappaB-regulated inflammatory genes, iNOS, TNF-alpha, IL-1beta, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages. Lutein inhibited LPS-induced NF-kappaB activation, which highly correlated with its inhibitory effect on LPS-induced IkappaB kinase (IKK) activation, IkappaB degradation, nuclear translocation of NF-kappaB, and binding of NF-kappaB to the kappaB motif of the iNOS promoter. This compound inhibited LPS- and H(2)O(2)-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-kappaB-inducing kinase (NIK), and Akt phosphorylation, which are all upstream of IKK activation, but did not affect the interaction between Toll-like receptor 4 and MyD88 and the activation of mitogen-activated protein kinases. The NADPH oxidase inhibitor apocynin and gp91(phox) deletion reduced the LPS-induced NF-kappaB signaling pathway as lutein did. Moreover, lutein treatment and gp91(phox) deletion decreased the expressional levels of the inflammatory genes in vivo and protected mice from LPS-induced lethality. Our data suggest that H(2)O(2) modulates IKK-dependent NF-kappaB activation by promoting the redox-sensitive activation of the PI3K/PTEN/Akt and NIK/IKK pathways. These findings further provide new insights into the pathophysiological role of intracellular H(2)O(2) in the NF-kappaB signal pathway and inflammatory process.

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Crossref · 10.1016/j.freeradbiomed.2008.06.019

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  • H2O2 acts downstream of TLR4 signalling, specifically to activate NFκB signalling.

    “Since TLR4 signalling mediates the macrophage and microglial LPS response, which includes MAPK activation, it is suggested that H2O2 acts downstream of TLR4 signalling, specifically to activate NFκB signalling.”
  • 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].”

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Authors
Kim, J.-H., Na, H.-J., Kim, C.-K., Kim, J.-Y., Ha, K.-S., Lee, H., Chung, H.-T., Kwon, H. J., Kwon, Y.-G., & Kim, Y.-M.
Affiliations
  • Kangwon National University (KR)
  • Wonkwang University (KR)
  • Yonsei University (KR)
Corresponding author
Kim, Young-Myeong
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2008-09
Volume
45
Issue
6
Pages
885-896
ISSN
0891-5849 (ISSN-L)
OpenAlex
W2068826328
Cited by
273
References
50
Citations by year
2026: 14 · 2025: 12 · 2024: 9 · 2023: 14 · 2022: 20 · 2021: 20 · 2020: 14 · 2019: 18 · 2018: 13 · 2017: 18 · 2016: 13 · 2015: 14 · 2014: 14 · 2013: 21 · 2012: 21
FWCI
4.33
Type
journal article
Language
en
Open access
closed
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
lutein, NF-κB activation, hydrogen peroxide, reactive oxygen species, lipopolysaccharide, macrophages, inflammation, NADPH oxidase, gp91phox, apocynin, TLR4, MyD88, inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, IL-1β, carotenoids
MeSH terms
Animals, Anti-Inflammatory Agents, Base Sequence, Gene Expression Regulation, Hydrogen Peroxide, Oxidation-Reduction, Lutein, NF-kappa B, Macrophages, Peritoneal, DNA Primers, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Chromatin Immunoprecipitation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice

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