Interleukin-6 is required for cell cycle arrest and activation of DNA repair enzymes after partial hepatectomy in mice.
BACKGROUND
Interleukin-6 (IL-6) has been shown to be vital for liver regeneration, however the specific mechanisms and factors involved remain incompletely defined. The present study aimed to investigate whether IL-6 exerts its protective effects via arresting the cell cycle allowing base excision and repair of oxidized DNA after hepatectomy.


RESULTS
Following seventy percent partial hepatectomy (PH) in wild type (WT) mice IL-6 serum levels increased reaching peak levels at 3 hours. This was associated with markers of cell cycle arrest as p21 expression was increased and cyclin D1 and proliferating cell nuclear antigen (PCNA) expression decreased. In the absence of IL-6, markers of cell cycle arrest were absent and the number of bromodeoxyuridine (BrdU) positive cells was significantly higher at 28, 32 and 36 hours after PH. The mRNAs for DNA repair enzymes, including Neil-1, 8-oxodGTPase, OGG1, Apex1, and UDG (DNA glycosylase) were increased 2 to 4 fold in WT mice at 6 and/or 12 hours after PH compared to IL-6 knockout (KO) mice. The protein levels of Neil1 and OGG1 were also significantly increased in WT mice compared to KO mice. Pathological changes were far greater and survival was less in IL-6 KO mice than in WT mice. Administration of IL-6 in KO mice restored p21 and DNA repair enzyme expression to wild-type levels and survival was improved.


CONCLUSIONS
IL-6 caused cell cycle arrest and delayed proliferation during the first day after PH. This delay was associated with the activation of DNA repair enzymes resulting in accurate replication and restoration of hepatic mass.
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.|Department of Surgery, Tokyo Medical University, Shinjuku, Tokyo, Japan.
Shingo
S
Tachibana
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.|School of Life Science, Tianjin University, Tianjin, China.
Xiuying
X
Zhang
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.|Department of Surgery, Tokyo Medical University, Shinjuku, Tokyo, Japan.
Kazushige
K
Ito
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.
Yoshihiro
Y
Ota
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.
Andrew M
AM
Cameron
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.
George Melville
GM
Williams
Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 771, Baltimore, MD 21205, USA.
Zhaoli
Z
Sun