Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration.
After tissue loss the liver has the unique capacity to restore its mass by hepatocyte proliferation. Interleukin-6 (IL6)-deficient mice show a lack in DNA synthesis after partial hepatectomy (PH). To define better the role of IL6 and its family members for liver regeneration after PH, we used conditional knockout mice for glycoprotein 130 (gp130), the common signal transducer of all IL6 family members. We show that gp130-dependent pathways control Stat3 activation after PH. By using gene array analysis, we demonstrate that c-jun, NF-kappa B, c-myc, and tumor necrosis factor receptor expression is gp130-dependent. However, in gp130-deleted mice only minor effects on cell cycle and on the maximum of DNA synthesis after PH were found compared with controls. As in conditional gp130 animals, the acute phase response was completely abolished, we considered that other means are essential to define the role of gp130-dependent pathways for liver regeneration. LPS stimulation in gp130-deleted and also IL6 -/- animals after PH leads to a significant reduction in survival and DNA synthesis, which was associated with decreased Bcl-xL expression and higher apoptosis in the liver. These results indicate that the phenotype concerning the reduction in DNA synthesis might be linked to the degree of infection after PH. Thus our results suggest that the role of gp130-dependent signaling is not a direct influence on cell cycle progression after partial hepatectomy but is to activate protective pathways important to enable hepatocyte proliferation.
Wuestefeld
Torsten
T
Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Klein
Christian
C
Streetz
Konrad L
KL
Betz
Ulrich
U
Lauber
Jörg
J
Buer
Jan
J
Manns
Michael P
MP
Müller
Werner
W
Trautwein
Christian
C
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001483:Base Sequence; D050822:Cytokine Receptor gp130; D017931:DNA Primers; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D017781:Genes, Immediate-Early; D006498:Hepatectomy; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D015703:Antigens, CD; D017931:DNA Primers; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130