Acute-phase response factor, increased binding, and target gene transcription during liver regeneration.
OBJECTIVE
The acute-phase response may contribute and influence cell-cycle progression in hepatocytes. The aim of this study was to examine the regulation of the alpha 2-macroglobulin gene during liver regeneration and molecular mechanisms that influence its expression.


METHODS
Partial hepatectomy or sham surgery was performed in Sprague-Dawley rats. At different time points after surgery blood was taken from the liver vein, and nuclear extracts and RNA were prepared. Northern blot analysis, run-off assays, gel shift experiments, and cytokine assays were performed.


RESULTS
Increased transcription of the alpha 2-macroglobulin gene was found 12-24 hours posthepatectomy and not after sham surgery. Increased levels of alpha 2-macroglobulin messenger RNA correlated with enhanced binding of acute-phase response factor/signal transducer and activator of transcription 3 (APRF/Stat3) towards the cognate DNA sequence in the alpha 2-macroglobulin promoter and dramatically increased interleukin-6 levels in the liver vein. In contrast, nuclear translocation of APRF/Stat3 was detected as early as 1 hour after hepatectomy and up to 48 hours posthepatectomy. Therefore, two events can be distinguished in the regulation of APRF/Stat3: Its nuclear translocation and increased DNA binding.


CONCLUSIONS
Increased alpha 2-macroglobulin transcription posthepatectomy is achieved by increased levels of interleukin 6 and consecutive binding of APRF/Stat3 to the alpha 2-macroglobulin promoter. A two-step event is suggested for APRF/Stat3-dependent gene activation in hepatocytes.
Trautwein
C
C
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Rakemann
T
T
Niehof
M
M
Rose-John
S
S
Manns
M P
MP
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D015850:Interleukin-6 / Q000097:blood; D008115:Liver Regeneration; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D011184:Postoperative Period; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000511:alpha-Macroglobulins / Q000235:genetics
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D000511:alpha-Macroglobulins