Autonomic regulation of liver regeneration after partial hepatectomy in mice.
OBJECTIVE
The autonomic vagus nerve is thought to play an essential role in liver regeneration since hepatic vagotomy delays hepatic DNA synthesis. However, how the parasympathetic vagus nerve is involved in liver regeneration remains obscure. Kupffer cells are located in liver sinusoids adjacent to hepatocytes and might regulate liver regeneration by releasing interleukin-6 (IL-6). The present study examines the role of the vagus nerve and how Kupffer cells are involved in parasympathetic nerve-mediated liver regeneration in mice.


METHODS
We performed surgical vagotomy of the hepatic branch and then partial hepatectomy (PH); some mice received acetylcholine (ACh) agonist/antagonist before PH. We then evaluated liver regeneration and signal transducer and activator of transcription-3 (STAT3) activation. We also investigated whether ACh stimulates IL-6 release from Kupffer cells.


RESULTS
Surgical vagotomy impaired liver regeneration. STAT3, which is activated by IL-6 after hepatectomy and plays a pivotal role in liver regeneration, was less activated in vagotomized mice after PH. Post-PH STAT3 activation was recovered by administering vagotomized mice with an ACh agonist. Furthermore, ACh stimulated IL-6 release in Kupffer cells in vitro.


CONCLUSIONS
The parasympathetic system (vagus nerve) contributes to liver regeneration after hepatectomy by stimulating IL-6 release from Kupffer cells followed by STAT3 activation in hepatocytes.
Ikeda
Osamu
O
Department of Surgery, Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Ozaki
Michitaka
M
Murata
Soichiro
S
Matsuo
Ryota
R
Nakano
Yoritaka
Y
Watanabe
Motonobu
M
Hisakura
Katsuji
K
Myronovych
Andriy
A
Kawasaki
Takuya
T
Kohno
Keisuke
K
Ohkohchi
Nobuhiro
N
D000199:Actins / Q000235:genetics; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D018929:Cell Culture Techniques; D002455:Cell Division; D006498:Hepatectomy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000294:innervation; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014628:Vagotomy / Q000379:methods
D000199:Actins; D015850:Interleukin-6