Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration.
OBJECTIVE
Liver regeneration after loss of hepatic tissue leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Interleukin (IL)-6 is a key inducer of transcription factors involved in liver regeneration. Whenever IL-6 activates target cells, it binds to a specific IL-6 receptor (IL-6R). The IL-6/IL-6R complex then associates with the signal transducer gp130, leading to activation of intracellular signaling.


METHODS
We have recently constructed the designer cytokine Hyper-IL-6 consisting of soluble IL-6R covalently linked to IL-6, which directly stimulates gp130 even in the absence of membrane-bound IL-6R. We compared the influence of IL-6 and Hyper-IL-6 on liver regeneration after partial hepatectomy in mice.


RESULTS
The IL-6/soluble IL-6 fusion protein Hyper-IL-6, but not IL-6 alone, led to an earlier onset of hepatocellular proliferation resulting in an acceleration of liver weight restoration. Also, during liver regeneration, soluble IL-6R levels were increased.


CONCLUSIONS
These results emphasize a central role for IL-6 and soluble IL-6R in liver regeneration and indicate a possible therapeutic potential for the designer cytokine Hyper-IL-6 in clinical situations associated with liver regeneration such as acute hepatic failure or resection of chronically damaged liver tissue.
Peters
M
M
Division of Pathophysiology, First Department of Medicine, University of Mainz, Mainz, Germany.
Blinn
G
G
Jostock
T
T
Schirmacher
P
P
Meyer zum Büschenfelde
K H
KH
Galle
P R
PR
Rose-John
S
S
D000818:Animals; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010766:Phosphorylation; D011184:Postoperative Period; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D012995:Solubility; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators