| Abstract | 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. |
| Authors | Y Kamohara, N Sugiyama, T Mizuguchi, D Inderbitzin, H Lilja, Y Middleton, T Neuman, A A Demetriou, J Rozga
(Affiliation: Liver Support Research Laboratory, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.)
|
| Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 273
Issue 1
Pg. 129-35
(Jun 24 2000)
ISSN: 0006-291X UNITED STATES |
| PMID | 10873574
(Publication Type: Journal Article)
|
| Copyright | Copyright 2000 Academic Press. |
| Chemical References |
- Antigens, CD
- Carrier Proteins
- DNA-Binding Proteins
- Il6st protein, rat
- Interleukin-6
- Membrane Glycoproteins
- NF-kappa B
- Proto-Oncogene Proteins
- RNA, Messenger
- Receptors, Interleukin-6
- Repressor Proteins
- STAT3 Transcription Factor
- Socs1 protein, mouse
- Socs1 protein, rat
- Stat3 protein, rat
- Suppressor of Cytokine Signaling Proteins
- Trans-Activators
- Transcription Factor AP-1
- Cytokine Receptor gp130
- Hepatocyte Growth Factor
- DNA
- Jak2 protein, mouse
- Jak2 protein, rat
- Janus Kinase 2
- Protein-Tyrosine Kinases
|
| Topics |
- Animals
- Antigens, CD
(metabolism)
- Carrier Proteins
(genetics)
- Cell Division
(drug effects)
- Cells, Cultured
- Cytokine Receptor gp130
- DNA
(biosynthesis, genetics, metabolism)
- DNA-Binding Proteins
(antagonists & inhibitors, metabolism)
- Hepatectomy
- Hepatocyte Growth Factor
(pharmacology)
- Interleukin-6
(blood, pharmacology)
- Janus Kinase 2
- Liver
(drug effects, metabolism, pathology, surgery)
- Liver Failure, Acute
(metabolism, pathology, surgery)
- Liver Regeneration
(drug effects)
- Male
- Membrane Glycoproteins
(metabolism)
- NF-kappa B
(metabolism)
- Necrosis
- Protein Binding
- Protein-Tyrosine Kinases
(metabolism)
- Proto-Oncogene Proteins
- RNA, Messenger
(genetics, metabolism)
- Rats
- Rats, Sprague-Dawley
- Receptors, Interleukin-6
(metabolism)
- Repressor Proteins
- STAT3 Transcription Factor
- Suppressor of Cytokine Signaling Proteins
- Trans-Activators
(antagonists & inhibitors, metabolism)
- Transcription Factor AP-1
(metabolism)
- Up-Regulation
(drug effects)
|
