Concanavalin A-induced liver injury triggers hepatocyte proliferation.
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.
Trautwein
C
C
Department of Gastroenterology and Hepatology, Medical Hochschule Hannover, 30625 Hannover, Germany. trautwein.christian@mh-hannover.de
Rakemann
T
T
Malek
N P
NP
Plümpe
J
J
Tiegs
G
G
Manns
M P
MP
D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A