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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Chronic systemic inflammation in nfkb1−/− mice progresses with age.
“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]
In “Severe Injury-Induced Hepatic Inflammation in Nfkb1−/− Mice,” the paper says spontaneous liver inflammation was not progressive: its severity did not change between 12 weeks and 1 year. The paper examines liver inflammation rather than systemic inflammation, so its age-comparison finding runs contrary to the progression attributed to it. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measurednfkb1−/− mice show enhanced responses to inflammatory stimuli and are thought to have a low-level elevated inflammatory phenotype.
“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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Research works printed but not linked: 2
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Gieling, R. G., Elsharkawy, A. M., Caamaño, J., Cowie, D. E., Wright, M. C., Ebrahimkhani, M. R., Burt, A. D., Mann, J., Raychaudhuri, P., Liou, H., et al. (2009) · Hepatology · doi:10.1002/hep.23385 · Cited by 57 · see citing works
Self-citationThe Impact of the Myeloid Response to Radiation Therapy
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Wilson, C. L., Murphy, L. B., Leslie, J., Kendrick, S. F. W., French, J., Fox, C. R., Sheerin, N., Fisher, A., Robinson, J. H., TINIAKOS, D. G., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.07.034 · Cited by 54 · see citing works
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M1 and M2 Functional Imprinting of Primary Microglia: Role of P2X7 Activation and miR-125b
Parisi, C., Napoli, G. D., Pelegrı́n, P., & Volonté, C. (2016) · Mediators of Inflammation · doi:10.1155/2016/2989548 · Cited by 50 · see citing works
Transcriptional regulation of stellate cell activation
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Altered circadian rhythm of the clock genes in fibrotic livers induced by carbon tetrachloride
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Allele-Specific Regulation of Matrix Metalloproteinase-3 Gene by Transcription Factor NFκB
Souslova, V., Townsend, P. A., Mann, J., van der Loos, C. M., Motterle, A., D’Acquisto, F., Mann, D. A., & Ye, S. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009902 · Cited by 43 · see citing works
Self-citationFlow-Induced Shear Stress Primes NLRP3 Inflammasome Activation in Macrophages via Piezo1
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Self-citationNF-κB signalling: Embracing complexity to achieve translation
Chakraborty, J. B., & Mann, D. A. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.10.030 · Cited by 41 · see citing works
Self-citationPerugorria, M. J., Murphy, L. B., Fullard, N., Chakraborty, J. B., Vyrla, D., Wilson, C. L., Oakley, F., Mann, J., & Mann, D. A. (2012) · Hepatology · doi:10.1002/hep.26108 · Cited by 41 · see citing works
Self-citationGao, Y., Zhang, H., Luo, L., Lin, J., Li, D., Zheng, S., Huang, H., Yan, S.-F., Yang, J., Yu, H., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700315 · Cited by 41 · see citing works
The c-Rel Subunit of NF-κB Regulates Epidermal Homeostasis and Promotes Skin Fibrosis in Mice
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Self-citationZafar, H., & Ali, S. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2012.11.008 · Cited by 40 · see citing works
Self-citationEndothelial NF-κB Blockade Abrogates ANCA-Induced GN
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c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis
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[6]-Gingerol dampens hepatic steatosis and inflammation in experimental nonalcoholic steatohepatitis
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Bandyopadhaya, A., Tsurumi, A., & Rahme, L. G. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01211 · Cited by 28 · see citing works
Bone marrow fails to differentiate into liver epithelium during murine development and regeneration†
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Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence
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Case Report: A Novel Mutation in NFKB1 Associated With Pyoderma Gangrenosum
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Polyphenols from Tamarix nilotica: LC–ESI-MSn Profiling and In Vivo Antifibrotic Activity
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Reshaping the chromatin landscape after spinal cord injury
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Moir, J. A. G., Long, A. K., Haugk, B., French, J., Charnley, R., Manas, D., Wedge, S. R., Mann, J., Robinson, S. M., & White, S. A. (2020) · Pancreas · doi:10.1097/mpa.0000000000001689 · Cited by 15 · see citing works
Self-citationA novel NFkB1 mutation linking pyoderma gangrenosum and common variable immunodeficiency
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Links between telomere dysfunction and hallmarks of aging
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Curcumin and its allied analogues: epigenetic and health perspectives - a review
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UNVEILING THE ANTICANCER EFFECT OF SYRINGIC ACID AND ITS DERIVATIVES IN HEPATOCELLULAR CARCINOMA
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Inflammation and Hepatotoxicity
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- 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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