Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.
Liver regeneration stimulated by a loss of liver mass leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Mice with targeted disruption of the interleukin-6 (IL-6) gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes of these mice but not in nonparenchymal liver cells. Furthermore, there were discrete G1 phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activator of transcription protein 3) activation and depressed AP-1, Myc, and cyclin D1 expression. Treatment of IL-6-deficient mice with a single preoperative dose of IL-6 returned STAT3 binding, gene expression, and hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative response.
Department of Genetics and Medicine, University of Pennsylvania School of Medicine, 705a Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
D E
DE
Cressman
L E
LE
Greenbaum
R A
RA
DeAngelis
G
G
Ciliberto
E E
EE
Furth
V
V
Poli
R
R
Taub
D000818:Animals; D019938:Cyclin D1; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase; D005786:Gene Expression Regulation; D018390:Gene Targeting; D017781:Genes, Immediate-Early; D006498:Hepatectomy; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000209:etiology* / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009154:Mutation; D009336:Necrosis; D015513:Oncogene Proteins / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis
D016213:Cyclins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D004247:DNA