Concanavalin A-induced liver injury triggers hepatocyte proliferation.
Open accessAbstract
Concanavalin A (Con A) injection into mice leads to immune-mediated liver injury. We studied whether after Con A-induced liver injury, TNF- and IL-6-dependent signaling pathways known to be related to hepatocyte proliferation are activated. 2 h after Con A injection, maximum TNF-alpha, and after 4-8 h, maximum IL-6 serum levels were found. The rise in aminotransferases and DNA fragmentation started after 4 h; maximum levels were evident after 8 h. 5-Bromo-2'-deoxyuridine staining and nuclear cyclin A expression as markers of the S-phase were first detected in hepatocyte nuclei after 24 h, peaking after 48 h. An increase in TNF-dependent nuclear expression of CCAAT/enhancer-binding protein-beta (C/EBP-beta)/liver-enriched activating protein (LAP) was detected after 1 h, whereas an increase in RNA expression was evident only after 4 h. C/EBP-beta/LAP expression returned to normal values before progression into the S-phase. DNA binding of signal transducer and activator of transcription (STAT) 3/acute phase response factor (APRF) increased for up to 8 h. As found by supershift experiments, in addition to STAT3/APRF, STAT1 also binds to the same sequence. During the course of time gel shift experiments, DNA binding of the apoptosis-related STAT1 started earlier than DNA binding of STAT3/APRF, which regulates hepatocyte proliferation. However, the subsequent decrease in DNA binding of both factors was comparable. This study demonstrates that after Con A injection, TNF- and IL-6- dependent signals trigger nuclear events regulating hepatocyte apoptosis and proliferation during liver injury.
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Luedde, T., Kubicka, S., Plümpe, J., Liedtke, C., Manns, M. P., & Trautwein, C. (2001) · Oncogene · doi:10.1038/sj.onc.1204690 · Cited by 23 · see citing works
“ALT and AST activities in plasma were determined by an automated enzyme assay as described before (Trautwein et al., 1998).”
MethodSelf-citationHuang, W., Dong, Z., Wei, H., Ding, C., Sun, R., & Tian, Z. (2006) · Liver International · doi:10.1111/j.1478-3231.2005.01221.x · Cited by 21 · see citing works
“A sufficient dose of Con A (15 mg/g body weight) could induce an NKT cell-dependent liver injury in mice (18, 19), in which severe liver injury also triggers liver regeneration 48 h following Con A injection (20).”
BackgroundThe ST2+ Treg/amphiregulin axis protects from immune-mediated hepatitis
Wachtendorf, S., Jonin, F., Ochel, A., Heinrich, F., Westendorf, A. M., Tiegs, G., & Neumann, K. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1351405 · Cited by 21 · see citing works
Self-citationFumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1
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“First, to assess feasibility, we induced acute liver damage in wild-type rabbits with concanavalin A (33), which causes a rapid regenerative response that facilitates engraftment of transplanted cells, and 24 h later 10(7) rabbit primary hepatocytes extracted from a healthy wild-type rabbit were injected intrasplenica…”
Ohta, S., Nakamuta, M., Fukushima, M., Kohjima, M., Kotoh, K., Enjoji, M., & Nawata, H. (2005) · Liver International · doi:10.1111/j.1478-3231.2005.01143.x · Cited by 19 · see citing works
“Second, the early increase in IL-6 levels at 6 h and decrease at 12 h in the Beraprost group might reflect the early regeneration of the liver, since IL-6 has been identified as an essential mediator of liver regeneration (39).”
BackgroundMultiphenotypic Whole-Cell Sensor for Viability Screening
Itle, L. J., & Pishko, M. V. (2005) · Analytical Chemistry · doi:10.1021/ac051012b · Cited by 17 · see citing works
Klevanski, M., Kim, H., Heilemann, M., et al. (2024) · Antiviral Research · doi:10.1016/j.antiviral.2024.105856 · Cited by 15 · see citing works
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“Con A-induced liver injury is characterized by markedly increasing of serum aminotransferase levels and massive infiltration of lymphocytes into the liver [23, 24].”
BackgroundWang, Y., Singh, R., Xiang, Y., Greenbaum, L. E., & Czaja, M. J. (2010) · Hepatology · doi:10.1002/hep.23929 · Cited by 14 · see citing works
Suh, H. N., Lee, S. H., Lee, M. Y., Lee, Y. J., Lee, J., & Han, H. J. (2008) · Cellular Physiology and Biochemistry · doi:10.1159/000185551 · Cited by 14 · see citing works
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“Simultaneously, based on the genomic DNA fragmentation analysis [16], hepatocytes demonstrated obvious apoptosis at 8 h as compared with the control group, and even more serious at 24 h, whereas the apoptosis decreased markedly at 72 h (Fig.”
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Shim, J.-U., & Lim, K. (2008) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2008.06.005 · Cited by 12 · see citing works
Mechanisms of Acute Liver Failure
Trautwein, C., & Koch, A. H. (2013) · Springer eBooks · doi:10.1007/978-3-319-02096-9_25 · Cited by 11 · see citing works
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“Previous studies have indicated that the early increase in cytokine levels is pivotal in triggering liver damage, because maximal levels of most cytokines are reached before infiltrating of the activated T lymphocytes occurs, but liver damage has already begun (9, 18).”
BackgroundResposta imune a Candida albicans
Costa, I. C., Felipe, I., & Gaziri, L. C. J. (2008) · Semina Ciências Biológicas e da Saúde · doi:10.5433/1679-0367.2008v29n1p27 · Cited by 8 · see citing works
Rapamycin prevents Concanavalin A‐induced liver injury by inhibiting lymphocyte activation
Zhang, Y., Xiao, X., Li, X., & Wei, H. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.05866.x · Cited by 8 · see citing works
Exploring the roles of non-coding RNAs in liver regeneration
Li, P., Ma, X., Huang, D., & Gu, X. (2024) · Non-coding RNA Research · doi:10.1016/j.ncrna.2024.04.003 · Cited by 8 · see citing works
Liver Protection by Bis(Maltolato)Zinc(II) Complex
Kawase, M., Kagaya, N., AKAMATSU, S.-I., Kamiyoshi, A., Shin-ichi, M. U. T. O., Tagawa, Y., & Yagi, K. (2004) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.53.1 · Cited by 7 · see citing works
“IL-6 seems to both harm and protect hepatocytes during ConA-induced hepatitis [9, 25, 34, 35, 38].”
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Mechanisms of Acute Liver Failure
Trautwein, C., & Koch, A. H. (2020) · Springer eBooks · doi:10.1007/978-3-030-51709-0_29 · Cited by 5 · see citing works
“In animal models of ALF, the IL-6 serum levels are also greatly increased [107], and treatment with a hyper-IL-6 designer molecule reduces liver cell damage in several animal models [108, 109].”
BackgroundSelf-citationSTAT Activation in the Acute Phase Response
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Animal Models of Autoimmune Liver Diseases
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“Immunosuppression in a state of remission/regeneration, i.e., 48 h after ConA administration ( 27 ,60), with respect to thymus-dependent antibody response, as seems to occur in AIH and EAH, has been reported (60–62), and, 1wk after a first ConA treatment, mice develop tolerance against immunemediated liver injury upon…”
BackgroundSelf-citationMechanisms of Acute Liver Failure
Trautwein, C., & Koch, A. H. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-518-3_28 · Cited by 1 · see citing works
“Consecutively CD4-positive and polymorphonuclear cells are attracted to the hepatic sinus and trigger an increase of cytokines like TNF, IL-2, IFN- IL-6, granulocyte macrophage colony-stimulation factor (GM-CSF) and IL-1 (58).”
BackgroundSelf-citationRegulation of Death Receptor-Mediated Cell Demise by Glutathione
Hentze, H. (2000)
Differentiation of mesenchymal stem cells (MSCs) into hepatocytes in acute liver injury
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“The hepatoprotective effect of IL-6 treatment is extended to Concanavalin A-induced T cell dependent liver failure through activating the STAT-3 signaling pathway and initiating the DNA synthesis response [24].”
BackgroundDevelopment of Animal Models to Study Idiosyncratic Drug-induced Liver Injury
Liu, F. (2015) · TSpace (University of Toronto)
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Acute liver failure — mechanisms of liver cell destruction
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Caractérisation de nouveaux inhibiteurs de la kinase RIPK1 et de la nécroptose
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“The tropism of ConA for the liver is determined by the intravenous route of administration, as the substance is transported in the blood and accumulates predominantly in the hepatic tissue [55].”
- Authors
- Trautwein, C., Rakemann, T., Malek, N. P., Plümpe, J., Tiegs, G., & Manns, M. P.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Venue
- Journal of Clinical Investigation
- Published
- 1998-05-01
- Volume
- 101
- Issue
- 9
- Pages
- 1960-1969
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508783
- OpenAlex
- W1964156956
- Cited by
- 87
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 3
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- concanavalin A, immune-mediated liver injury, hepatocyte proliferation, hepatocyte apoptosis, TNF-α, interleukin-6, STAT3, STAT1, cyclin A, S phase, transaminases, DNA fragmentation, liver injury
- MeSH terms
- Animals, Cell Cycle, Cell Nucleus, Concanavalin A, DNA-Binding Proteins, Liver, Liver Regeneration, Male, Mice, Inbred BALB C, Nuclear Proteins, Protein Binding, Tumor Necrosis Factor-alpha, Signal Transduction, Trans-Activators, Interleukin-6, Apoptosis, CCAAT-Enhancer-Binding Proteins, STAT3 Transcription Factor, Mice
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