PMID- 10960443
OWN - NLM
STAT- MEDLINE
DCOM- 20000914
LR  - 20151119
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 32
IP  - 3
DP  - 2000 Sep
TI  - Hyperstimulation with interleukin 6 inhibits cell cycle progression after 
      hepatectomy in mice.
PG  - 514-22
AB  - 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.
FAU - Wustefeld, T
AU  - Wustefeld T
AD  - Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, 
      Germany.
FAU - Rakemann, T
AU  - Rakemann T
FAU - Kubicka, S
AU  - Kubicka S
FAU - Manns, M P
AU  - Manns MP
FAU - Trautwein, C
AU  - Trautwein C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Biomarkers)
RN  - 0 (Cyclin A)
RN  - 0 (Cyclin E)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, Interleukin)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (interleukin 6-interleukin 6 receptor fusion protein, recombinant)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Cell Cycle/drug effects/physiology
MH  - Cyclin A/metabolism
MH  - Cyclin E/metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - *Hepatectomy
MH  - Humans
MH  - Interleukin-6/blood/genetics/*pharmacology
MH  - Mice
MH  - Mice, Transgenic/genetics/metabolism
MH  - Postoperative Period
MH  - Receptors, Interleukin/blood/genetics
MH  - Receptors, Interleukin-6
MH  - Recombinant Fusion Proteins/blood/genetics
MH  - S Phase/physiology
MH  - STAT3 Transcription Factor
MH  - Stimulation, Chemical
MH  - Time Factors
MH  - Trans-Activators/metabolism
MH  - rho GTP-Binding Proteins/metabolism
EDAT- 2000/08/29 11:00
MHDA- 2000/09/19 11:01
CRDT- 2000/08/29 11:00
PHST- 2000/08/29 11:00 [pubmed]
PHST- 2000/09/19 11:01 [medline]
PHST- 2000/08/29 11:00 [entrez]
AID - S0270-9139(00)53249-2 [pii]
AID - 10.1053/jhep.2000.16604 [doi]
PST - ppublish
SO  - Hepatology. 2000 Sep;32(3):514-22. doi: 10.1053/jhep.2000.16604.