Hyperstimulation with interleukin 6 inhibits cell cycle progression after hepatectomy in mice.
Interleukin 6 (IL-6) is an important mediator of hepatocyte proliferation after hepatectomy. However, elevated IL-6 levels are found in patients with chronic liver disease. Therefore, it is unclear if hyperstimulation with IL-6 may have an influence on liver regeneration. We investigated whether a strong activation of IL-6-dependent pathways may change the course of hepatocyte proliferation after hepatectomy. Transgenic mice overexpressing the human soluble IL-6 receptor/gp80 (hsgp80) in hepatocytes were stimulated with or without hepatectomy with human IL-6 (hIL-6). Nuclear extracts were prepared and activation of gp130-dependent pathways was studied by Western blot and gel shift experiments. Cell cycle progression of hepatocytes after hepatectomy was investigated by monitoring cell cycle-specific factors. hIL-6 strongly activates Stat3 for more than 48 hours in human soluble hsgp80 transgenic mice. In contrast, no major differences were evident in the regulation of the Ras/MAP kinase pathway compared with wild-type (wt) mice. Also when hsgp80 mice were stimulated with hIL-6 3 hours before hepatectomy Stat3 is activated for more than 72 hours, whereas in unstimulated mice this event is restricted to the early hours. Strong activation of Stat3 resulted in a delay and inhibition of hepatocyte proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) staining and Cyclin A and E expression. This observation directly correlates with the induction of the cell cycle inhibitor p21. In summary, strong IL-6-dependent activation of Stat3 before hepatectomy results in delay and inhibition of cell cycle progression after hepatectomy. Therefore our results suggest that hyperstimulation with IL-6 can inhibit liver regeneration.
Wüstefeld
T
T
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Rakemann
T
T
Kubicka
S
S
Manns
M P
MP
Trautwein
C
C
D000818:Animals; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006498:Hepatectomy; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D011184:Postoperative Period; D018123:Receptors, Interleukin / Q000097:blood / Q000235:genetics; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics; D016196:S Phase / Q000502:physiology; D050796:STAT3 Transcription Factor; D013268:Stimulation, Chemical; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015415:Biomarkers; D019925:Cyclin A; D019927:Cyclin E; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant; D020741:rho GTP-Binding Proteins