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Lipopolysaccharide-Induced Expression of NAD(P)H:Quinone Oxidoreductase 1 and Heme Oxygenase-1 Protects against Excessive Inflammatory Responses in Human Monocytes
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Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines TNF-α and IL-1β. The transcription factor NF-E2-related factor 2 (Nrf2) regulates innate immune responses in various experimental disease models. Presently, the role of Nrf2-regulated genes in LPS-treated human monocytes is not well defined. Herein we show that Nrf2 mediates a significant regulation of LPS-induced inflammatory responses. Analysis of Nrf2-regulated gene expression in human monocytes showed that LPS induced the expression of the phase II detoxification gene NAD(P)H:quinone oxidoreductase 1 (NQO1). Furthermore, NQO1 mRNA or protein expression in response to LPS was regulated by Nrf2. Silencing Nrf2 expression in human monocytes inhibited LPS-induced NQO1 expression; however, in contrast, it significantly increased TNF and IL-1β production. Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced TNF and IL-1β expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1β expression. These results show for the first time that LPS induces NQO1 and HO-1 expression in human monocytes via Nrf2 to modulate their inflammatory responsiveness, thus providing novel potential therapeutic strategies for the treatment of sepsis.
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“Nrf2 plays a role in regulating the anti-inflammatory response through redox control and activation of ARE-mediated anti-inflammatory genes, including the expression of the antioxidant genes NQO1, HO-1, and PRX1, all of which exhibit anti-inflammatory effects [191,192,193,194].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [193]
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Metadata
- Authors
- Rushworth, S. A., MacEwan, D. J., & O’Connell, M. A.
- Affiliations
- University of East Anglia (GB)
- School of Chemical Sciences and Pharmacy, University of East Anglia , Norwich,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-11
- Volume
- 181
- Issue
- 10
- Pages
- 6730-6737
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2923058
- OpenAlex
- W2105691693
- Cited by
- 215
- References
- 51
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 12 · 2023: 8 · 2022: 14 · 2021: 12 · 2020: 18 · 2019: 11 · 2018: 8 · 2017: 14 · 2016: 8 · 2015: 16 · 2014: 17 · 2013: 13 · 2012: 11
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- University of East Anglia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- lipopolysaccharide, NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1, Nrf2, human monocytes, sepsis, inflammation, TNF-α, IL-1β, innate immunity
- MeSH terms
- Cell Line, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Monocytes, RNA, Messenger, Tumor Necrosis Factor-alpha, Gene Expression, NAD(P)H Dehydrogenase (Quinone), Reactive Oxygen Species, Sepsis, Reverse Transcriptase Polymerase Chain Reaction, Gene Silencing, NF-E2-Related Factor 2, Heme Oxygenase-1, Interleukin-1beta
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