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Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in
C Trautwein1, T Rakemann, D A Brenner
1Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Hannover, Germany.
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.
Insights
Concanavalin A (con A) triggers tumor necrosis factor (TNF)-dependent liver cell death, activating Jun kinase (JNK) and nuclear factor-kappaB (NF-κB) pathways. Blocking TNF with anti-TNF inhibits these pathways, offering therapeutic potential.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Concanavalin A (con A) administration induces hepatocyte apoptosis, mimicking human immune-mediated fulminant hepatic failure.
- Tumor necrosis factor (TNF) signaling pathways are critical, leading to apoptosis, nuclear factor-kappaB (NF-κB) translocation, or Jun kinase (JNK) activation.
Purpose of the Study:
- To investigate the specific TNF-dependent intracellular pathways activated following con A injection in vivo.
- To elucidate the temporal relationship between JNK and NF-κB activation in this model.
Main Methods:
- BALB/c mice were injected with con A, con A plus anti-TNF, or control buffer.
- Techniques included immunofluorescence, Western blot, Northern blot, gel shift assays, and measurement of Erk and JNK activity and DNA fragmentation.
Main Results:
- Con A induced hepatocyte DNA fragmentation between 4-24 hours post-injection.
- JNK activation peaked (>20-fold) immediately after con A, while NF-κB translocation was maximal at 4 hours.
- Anti-TNF treatment blocked all investigated pathways, though c-Jun nuclear expression and DNA binding persisted despite anti-TNF therapy.
Conclusions:
- TNF-dependent pathway activation is intrinsically linked to hepatocyte apoptosis in the con A model.
- Targeting these pathways in vivo holds promise for developing novel therapeutic strategies against liver apoptosis.
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