Concanavalin A—induced liver cell damage: Activation of intracellular pathways triggered by tumor necrosis factor in mice☆☆☆
Open accessAbstract
Background & aims Concanavalin A (con A) induces tumor necrosis factor (TNF)-dependent hepatocyte apoptosis resembling immune-mediated fulminant hepatic failure in humans. Intracellular pathways originating at the TNF receptor are either linked to apoptosis, nuclear factor (NF)-kappaB translocation, or Jun kinase (JNK) activation. The aim of this study was to study TNF-dependent pathways after con A injection in vivo.Methods Con A, con A plus anti-TNF, and control buffer were injected into BALB/c mice. Immunofluorescence, Western blot, Northern blot, gel shift, Erk, and JNK activity and DNA fragmentation experiments were performed at different time points after injection.Results DNA fragmentation in hepatocytes was increased 4-24 hours after con A injection. JNK was activated maximally (>20-fold) directly after con A injection, whereas binding and nuclear translocation of NF-kappaB was maximal after 4 hours. All pathways were blocked by anti-TNF. JNK activation was specific because related ERK 1 + 2 were not activated after con A. High nuclear expression of c-Jun was already evident 1 hour after con A injection; however, in contrast to JNK, anti-TNF treatment did not block c-Jun nuclear expression and DNA binding.Conclusions In the con A model, activation of TNF-dependent pathways is associated with apoptosis of hepatocytes. Their modulation in vivo may have implications to develop new therapeutic strategies to prevent apoptosis.
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During early stages of Con A-induced hepatitis, TNFα and IFNγ directly mediate liver cell damage.
“During the early stages, TNFα and IFNγ directly mediate liver cell damage (11).”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [11]
The introduction (page not supplied) reports that TNF levels rise early after Con A injection and that anti-TNF treatment blocks liver injury. The Discussion (page not supplied) says IFNγ is critical for apoptosis but finds no clear evidence that it directly induces it; the authors consider it more likely to modulate TNF-triggered pathways. Thus, the claim that both cytokines directly mediate early liver cell damage overstates the source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCcn1dm/dm mice are substantially resistant to concanavalin A-induced, TNF-α-dependent hepatocyte apoptosis.
“Ccn1dm/dm mice are substantially resistant to concanavalin A-induced, TNF-α-dependent hepatocyte apoptosis [107,108].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [107]
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References 40 · Cited by 147
Research works printed but not linked: 3
- Hunter T, Karin M. Control of transcription factor activity by protein phosphorylation. Cell 1992;70:375-387.
- Ku ¨sters S, Grell M, Ku ¨nstle G, Kollias G, Blu ¨thmann H, Tiegs G. The role of membrane-bound TNF in concanavalin A-induced T cell-dependent liver injury in mice (abstr). Arch Pharm 1997;355: R85.
- Itoh N, Yonehara S, Ishii A, Yonehara M, Mizuchima SI, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface Fas can mediate apoptosis. Cell 1991;66:2333-2343.
- Authors
- Trautwein, C., Rakemann, T., Brenner, D. A., Streetz, K., Licato, L., Manns, M. P., & Tiegs, G.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 1998-05
- Volume
- 114
- Issue
- 5
- Pages
- 1035-1045
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2147700544
- Cited by
- 147
- References
- 40
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 6 · 2014: 2 · 2013: 2 · 2012: 5
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- concanavalin A, TNF-α, hepatocyte apoptosis, acute liver failure, TNF receptor signaling, NF-κB nuclear translocation, JNK activation, c-Jun, ERK1/2, anti-TNF therapy, hepatocyte injury
- MeSH terms
- Animals, Biological Transport, Cell Nucleus, Concanavalin A, DNA, Enzyme Activation, Intracellular Membranes, Liver, Lymphocyte Activation, Male, Mice, Inbred BALB C, Protein Kinases, T-Lymphocytes, Tumor Necrosis Factor-alpha, NF-kappa B, Proto-Oncogene Proteins c-jun, Apoptosis, Mitogen-Activated Protein Kinase Kinases, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice
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