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
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [146]
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 [146]
Cites
Oxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413 · see citing works
Function and Activation of NF-kappaB in the Immune System
Baeuerle, P. A., & Henkel, T. (1994) · Annual Review of Immunology · doi:10.1146/annurev.iy.12.040194.001041 · Cited by 4,745 · see citing works
Nuclear Factor-κB — A Pivotal Transcription Factor in Chronic Inflammatory Diseases
Barnes, P. J., & Karin, M. (1997) · New England Journal of Medicine · doi:10.1056/nejm199704103361506 · Cited by 4,622 · see citing works
NF-κB: a key role in inflammatory diseases
Tak, P. P., & Firestein, G. S. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11830 · Cited by 3,918 · see citing works
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
O'Neill, L. A. J., & Bowie, A. G. (2007) · Nature Reviews Immunology · doi:10.1038/nri2079 · Cited by 2,667 · see citing works
Lycopene as the most efficient biological carotenoid singlet oxygen quencher
Mascio, P. D., Kaiser, S., & Sies, H. (1989) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(89)90467-0 · Cited by 2,238 · see citing works
NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase
Özeş, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B. (1999) · Nature · doi:10.1038/43466 · Cited by 2,175 · see citing works
Cantley, L. C., & Neel, B. G. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.8.4240 · Cited by 2,007 · see citing works
NF-κB is a target of AKT in anti-apoptotic PDGF signalling
Romashkova, J. A., & Makarov, S. S. (1999) · Nature · doi:10.1038/43474 · Cited by 1,847 · see citing works
Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate
Franke, T. F., Kaplan, D., Cantley, L., & Toker, A. (1997) · Science · doi:10.1126/science.275.5300.665 · Cited by 1,609 · see citing works
Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer
Yamamoto, Y., & Gaynor, R. B. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11914 · Cited by 1,581 · see citing works
NF-κB activation by reactive oxygen species: Fifteen years later
Gloire, G., Legrand-Poels, S., & Piette, J. G. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.04.011 · Cited by 1,540 · see citing works
Vitamins E and C, beta-carotene, and other carotenoids as antioxidants
Sies, H., & Stahl, W. (1995) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/62.6.1315s · Cited by 1,075 · see citing works
Reversible Inactivation of the Tumor Suppressor PTEN by H2O2
Lee, S.-R., Yang, K., Kwon, J., Lee, C., Jeong, W., & Rhee, S. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111899200 · Cited by 1,061 · see citing works
Traenckner, E. B.-M., Pahl, H. L., Henkel, T., Schmidt, K. N., Wilk, S., & Baeuerle, P. A. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07287.x · Cited by 1,014 · see citing works
Griendling, K. K., Sorescu, D., Lassegue, B. P., & Ushio‐Fukai, M. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.10.2175 · Cited by 955 · see citing works
Positive and Negative Regulation of IκB Kinase Activity Through IKKβ Subunit Phosphorylation
Delhase, M., Hayakawa, M., Chen, Y., & Karin, M. (1999) · Science · doi:10.1126/science.284.5412.309 · Cited by 852 · see citing works
Antioxidant Functions of Vitamins
Sies, H., Stahl, W., & Sundquist, A. R. (1992) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1992.tb17085.x · Cited by 827 · see citing works
β-Carotene and Other Carotenoids as Antioxidants
de Paiva, S. A. R., & Russell, R. M. (1999) · Journal of the American College of Nutrition · doi:10.1080/07315724.1999.10718880 · Cited by 825 · see citing works
Park, H. S., Jung, H. Y., Park, E. Y., Kim, J., Lee, W. J., & Bae, Y. S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.6.3589 · Cited by 635 · see citing works
Self-citationInvolvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB
Asehnoune, K., Strassheim, D., Mitra, S., Kim, J. Y., & Abraham, E. H. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.4.2522 · Cited by 564 · see citing works
Self-citationNF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176
Lei, L., Cao, Z., & Goeddel, D. V. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.7.3792 · Cited by 536 · see citing works
Lee, J. Y., Ye, J., Gao, Z., Youn, H. S., Lee, W. H., Zhao, L., Sizemore, N., & Hwang, D. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305213200 · Cited by 524 · see citing works
Epidermal Growth Factor Receptor-dependent Akt Activation by Oxidative Stress Enhances Cell Survival
Wang, X., McCullough, K. D., Franke, T. F., & Holbrook, N. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14624 · Cited by 461 · see citing works
Chemistry, physiology and pathology of free radicals
Bergendi, L., Beneš, L., Ďuračková, Z., & Ferencĭk, M. (1999) · Life Sciences · doi:10.1016/s0024-3205(99)00439-7 · Cited by 439 · see citing works
A Fourth IκB Protein within the NF-κB Signaling Module
Basak, S., Kim, H., Kearns, J. D., Tergaonkar, V., O'Dea, E. L., Werner, S. L., Benedict, C. A., Ware, C. F., Ghosh, G., Verma, I. M., et al. (2007) · Cell · doi:10.1016/j.cell.2006.12.033 · Cited by 404 · see citing works
Pomerantz, J. L., & Baltimore, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00697-4 · Cited by 395 · see citing works
Evidence that reactive oxygen species do not mediate NF‐κB activation
Hayakawa, M., Miyashita, H., Sakamoto, I., Kitagawa, M., Tanaka, H., Yasuda, H., Karin, M., & Kikugawa, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg332 · Cited by 381 · see citing works
Lee, S., Bai, S.-K., Lee, K.-S., Namkoong, S., Na, H. J., Ha, K., Han, J. A., Yim, S. V., Chang, K., Kwon, Y. G., et al. (2003) · PubMed · Cited by 279 · see citing works
Self-citationBai, S.-K., Lee, S.-J., Na, H.-J., Ha, K.-S., Han, J.-A., Lee, H., Kwon, Y.-G., Chung, C.-K., & Kim, Y.-M. (2005) · Experimental & Molecular Medicine · doi:10.1038/emm.2005.42 · Cited by 269 · see citing works
Self-citationZhang, W., Hao, W., Hagen, T. M., & Frei, B. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700305104 · Cited by 258 · see citing works
Kefaloyianni, E., Gaitanaki, C., & Beis, I. D. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2006.05.004 · Cited by 256 · see citing works
Lee, S., Bai, S.-K., Lee, K., Namkoong, S., Na, H.-J., Ha, K., Han, J., Yim, S., Chang, K., Kwon, Y., et al. (2003) · Molecules and Cells · doi:10.1016/s1016-8478(23)13772-1 · Cited by 247 · see citing works
Self-citationRamakrishnan, P., Wang, W., & Wallach, D. (2004) · Immunity · doi:10.1016/j.immuni.2004.08.009 · Cited by 232 · see citing works
Li, Q., & Engelhardt, J. F. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511153200 · Cited by 219 · see citing works
Syrovets, T., Büchele, B., Krauss, C., Laumonnier, Y., & Simmet, T. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.1.498 · Cited by 193 · see citing works
Jang, S. I., Kim, H. J., Kim, Y., Jeong, S.-I., & You, Y. (2006) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2006.04.044 · Cited by 181 · see citing works
Self-citationBhattacharyya, S., Sen, P., Wallet, M. A., Long, B., Baldwin, A. S., & Tisch, R. (2004) · Blood · doi:10.1182/blood-2003-12-4302 · Cited by 173 · see citing works
Regulation of the Akt kinase by interacting proteins
Du, K., & Tsichlis, P. N. (2005) · Oncogene · doi:10.1038/sj.onc.1209099 · Cited by 144 · see citing works
Hasan, R. N., & Schafer, A. I. (2007) · Circulation Research · doi:10.1161/circresaha.107.155143 · Cited by 124 · see citing works
Inhibitory Effects of Lutein on Endotoxin-Induced Uveitis in Lewis Rats
Jin, X.-H., Ohgami, K., Shiratori, K., Suzuki, Y., Hirano, T., Koyama, Y., Yoshida, K., Ilieva, I. B., Iseki, K., & Ohno, S. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1429 · Cited by 121 · see citing works
Sasada, M., Pabst, M. J., & Johnston, R. B. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44543-1 · Cited by 119 · see citing works
Liu, S., Lin, X., Shi, D., Cheng, J., Wu, C., & Zhang, Y. (2002) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(02)00430-7 · Cited by 119 · see citing works
Han, Y.-J., Kwon, Y., Chung, H., et al. (2001) · Nitric Oxide · doi:10.1006/niox.2001.0367 · Cited by 91 · see citing works
Self-citationKoutsos, E. A., García-López, J. C., & Klasing, K. C. (2006) · Journal of Nutrition · doi:10.1093/jn/136.4.1027 · Cited by 83 · see citing works
Tu, V. C., Bahl, J. J., & Chen, Q. M. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.300.3.1101 · Cited by 83 · see citing works
Barhoumi, R., Faske, J. B., Liu, X., & Tjalkens, R. B. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2003.12.009 · Cited by 68 · see citing works
Fischer, C., Page, S., Weber, M., Eisele, T., Neumeier, D., & Brand, K. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.35.24625 · Cited by 67 · see citing works
Na, H.-J., Lee, G., Oh, H.-Y., Jeon, K. S., Kwon, H.-J., Ha, K., Lee, H., Kwon, Y., & Kim, Y.-M. (2006) · International Immunopharmacology · doi:10.1016/j.intimp.2006.06.004 · Cited by 64 · see citing works
Self-citationNa, H.-J., Lee, S., Kang, Y.-C., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.2.1276 · Cited by 42 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Ros and ros-mediated cellular signaling
Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y., & Dong, W. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/4350965 · Cited by 1,980 · see citing works
Lingappan, K. (2018) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2017.11.002 · Cited by 1,051 · see citing works
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
“In LPS-stimulated macrophages, the peripheral cousins of microglia, the antioxidant lutein scavenges intracellular O2•– and H2O2 and reduces NFκB activation, whilst TLR4 signalling and MAPK activation remained [146].”
BackgroundLinking oxidative stress to inflammation: Toll-like receptors
Gill, R., Tsung, A., & Billiar, T. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.01.006 · Cited by 553 · see citing works
Park, J., Min, J.-S., Kim, B., Chae, U.-B., Yun, J. W., Choi, M.-S., Kong, I.-K., Chang, K.-T., & Lee, D.-S. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2014.10.016 · Cited by 529 · see citing works
Lutein: More than just a filter for blue light
Kijlstra, A., Tian, Y., Kelly, E. R., & Berendschot, T. T. J. M. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2012.03.002 · Cited by 349 · see citing works
Functional Properties of Spinach (Spinacia oleracea L.) Phytochemicals and Bioactives
Roberts, J. L., & Moreau, R. (2016) · Food & Function · doi:10.1039/c6fo00051g · Cited by 283 · see citing works
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
Yang, S., Qin, C., Hu, Z.-W., Zhou, L.-Q., Yu, H.-H., Chen, M., Bosco, D. B., Wang, W., Wu, L.-J., & Tian, D.-S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105290 · Cited by 232 · see citing works
Ye, D., Li, F. Y. L., Lam, K. S. L., Li, H., Jia, W., Wang, Y., Man, K., Lo, C. M., Li, X., & Xu, A. (2012) · Gut · doi:10.1136/gutjnl-2011-300269 · Cited by 206 · see citing works
Escribano-Lopez, I., Diaz-Morales, N., Iannantuoni, F., Lopez-Domenech, S., de Marañon, A. M., Abad-Jimenez, Z., Bañuls, C., Rovira-Llopis, S., Herance, J. R., Rocha, M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-34251-8 · Cited by 71 · see citing works
Carotenoids Improve Obesity and Fatty Liver Disease via Gut Microbiota: A Narrative Review
Hashemi, D., Fard, M. V., Mohammadhasani, K., Barati, M., & Nattagh‐Eshtivani, E. (2025) · Food Science & Nutrition · doi:10.1002/fsn3.70092 · Cited by 15 · see citing works
- 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
- ORCID
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review