Concanavalin A-induced liver injury triggers hepatocyte proliferation.
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Concanavalin A-induced liver injury triggers hepatocyte proliferation. / Trautwein, C; Rakemann, T; Malek, N P; Plümpe, J; Tiegs, Gisa; Manns, M P.
in: J CLIN INVEST, Jahrgang 101, Nr. 9, 9, 1998, S. 1960-1969.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Concanavalin A-induced liver injury triggers hepatocyte proliferation.
AU - Trautwein, C
AU - Rakemann, T
AU - Malek, N P
AU - Plümpe, J
AU - Tiegs, Gisa
AU - Manns, M P
PY - 1998
Y1 - 1998
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Signal Transduction
KW - Protein Binding
KW - Cell Cycle
KW - Cell Nucleus/metabolism
KW - Liver Regeneration
KW - Interleukin-6/metabolism
KW - Tumor Necrosis Factor-alpha
KW - CCAAT-Enhancer-Binding Proteins
KW - Concanavalin A/pharmacology
KW - DNA-Binding Proteins/metabolism
KW - Liver/cytology/drug effects
KW - Nuclear Proteins/metabolism
KW - STAT3 Transcription Factor
KW - Trans-Activators/metabolism
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Signal Transduction
KW - Protein Binding
KW - Cell Cycle
KW - Cell Nucleus/metabolism
KW - Liver Regeneration
KW - Interleukin-6/metabolism
KW - Tumor Necrosis Factor-alpha
KW - CCAAT-Enhancer-Binding Proteins
KW - Concanavalin A/pharmacology
KW - DNA-Binding Proteins/metabolism
KW - Liver/cytology/drug effects
KW - Nuclear Proteins/metabolism
KW - STAT3 Transcription Factor
KW - Trans-Activators/metabolism
M3 - SCORING: Journal article
VL - 101
SP - 1960
EP - 1969
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 9
M1 - 9
ER -
