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Nuclear Factor-κB1 (p50) Limits the Inflammatory and Fibrogenic Responses to Chronic Injury
Open accessAbstract
In this study we addressed the role of the nuclear factor (NF)-kappaB1/p50 subunit in chronic injury of the liver by determining the inflammatory and fibrotic responses of nfkappab1-null mice in an experimental model that mimics chronic liver disease. Mice received repeated hepatic injuries throughout 12 weeks by intraperitoneal injection of the hepatotoxin carbon tetrachloride. In response nfkappab1(-/-) mice developed more severe neutrophilic inflammation and fibrosis compared to nfkappab1(+/+) mice. This phenotype was associated with elevated hepatic expression of tumor necrosis factor (TNF)-alpha, which was localized to regions of the liver associated with inflammation and fibrosis. Hepatic stellate cells are important regulators of hepatic inflammatory and fibrogenic events but normally do not express TNF-alpha. Hepatic stellate cells derived from nfkappab1(-/-) mice expressed TNF-alpha promoter activity, mRNA, and protein. By contrast the expression of other NF-kappaB-responsive genes (ICAM1 and interleukin-6) was similar between nfkappab1(-/-) and nfkappab1(+/+) cells. We provide experimental evidence that the inappropriate expression of TNF-alpha by nfkappab1(-/-) cells is because of lack of a p50-dependent histone deacetylase 1 (HDAC1)-mediated repression of TNF-alpha gene transcription. Taken together these data indicate that the p50 NF-kappaB subunit plays a critical protective role in the injured liver by limiting the expression of TNF-alpha and its recruitment of inflammatory cells.
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“Together with published results212223 these data show that chronic systemic inflammation in nfkb1−/− mice progresses with age.”
From Chronic inflammation induces telomere dysfunction and accelerates ageing in mice (2014) · cites this paper as [21]
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“As a consequence nfkb1−/− mice, which are unable to form p50:p50 but can still generate RelA-containing NF-κB dimers, show enhanced responses to inflammatory stimuli2122 and are thought to have a low-level elevated inflammatory phenotype20.”
From Chronic inflammation induces telomere dysfunction and accelerates ageing in mice (2014) · cites this paper as [21]
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Metadata
- Authors
- Oakley, F., Mann, J., Nailard, S., Smart, D. E., Mungalsingh, N., Constandinou, C., Ali, S., Wilson, S. J., Millward-Sadler, H., Iredale, J. P., & Mann, D. A.
- Affiliations
- Southampton General Hospital (GB)
- Jamia Hamdard (IN)
- Corresponding author
- Mann, Derek A.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 166
- Issue
- 3
- Pages
- 695-708
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1602348
- OpenAlex
- W1992353205
- Cited by
- 123
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 8 · 2014: 7 · 2013: 10 · 2012: 10
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Wellcome Trust (050443, 068524)
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- chronic liver injury, liver fibrosis, neutrophilic inflammation, TNF-α, hepatic stellate cells, HDAC1, carbon tetrachloride hepatotoxicity, ICAM-1, interleukin-6
- MeSH terms
- Animals, Carbon Tetrachloride, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Fibrinogen, Fibrosis, Genotype, Histone Deacetylases, Immunohistochemistry, Inflammation, Liver, Male, Mice, Transgenic, Neutrophils, Phenotype, Plasmids, Promoter Regions, Genetic, RNA, Time Factors, Transcription Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha, Wound Healing, Immunoblotting, Genes, Reporter, Reverse Transcriptase Polymerase Chain Reaction, Mice, NF-kappa B p50 Subunit
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