Inhibition of signal transducer and activator transcription factor 3 in rats with acute hepatic failure.
In fulminant hepatic failure, survival is not possible without recovery of sufficient hepatocyte mass. Remarkably, only a few studies exist that provide insight into the mechanisms that control proliferation of residual hepatocytes after extensive hepatocyte loss. In this regard, the role of growth-regulatory factors, including pro-inflammatory cytokines such as interleukin-6 (IL-6), is not well understood. In the present study we show that in rats with critically low (10%) hepatocyte mass, whether with or without ongoing liver cell necrosis, inhibition of liver regeneration is associated with early and sustained increase in blood IL-6 levels. Under these conditions, the signal transducer and activator of transcription (Stat3) DNA binding activity was lowered at the time of G1/S cell-cycle transition. We further demonstrate that the protein inhibitor of activated Stat3 (PIAS3) and the suppressor of cytokine signaling (SOCS-1) were up-regulated early after induction of liver failure (6-12 h). In vitro, IL-6 induced PIAS3 expression in HGF stimulated rat hepatocytes. These findings suggest that after massive hepatocyte loss, an early and rapid rise in blood IL-6 levels may weaken the hepatic regenerative response through up-regulation of Stat3 inhibitors PIAS3 and SOCS-1.
Kamohara
Y
Y
Liver Support Research Laboratory, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
Sugiyama
N
N
Mizuguchi
T
T
Inderbitzin
D
D
Lilja
H
H
Middleton
Y
Y
Neuman
T
T
Demetriou
A A
AA
Rozga
J
J
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004247:DNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood / Q000494:pharmacology; D053614:Janus Kinase 2; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; C494088:Stat3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D050822:Cytokine Receptor gp130; D017228:Hepatocyte Growth Factor; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2