Opposing roles of gp130-mediated STAT-3 and ERK-1/ 2 signaling in liver progenitor cell migration and proliferation.
Gp130-mediated IL-6 signaling may play a role in oval cell proliferation in vivo. Levels of IL-6 are elevated in livers of mice treated with a choline-deficient ethionine-supplemented (CDE) diet that induces oval cells, and there is a reduction of oval cells in IL-6 knockout mice. The CDE diet recapitulates characteristics of chronic liver injury in humans. In this study, we determined the impact of IL-6 signaling on oval cell-mediated liver regeneration in vivo. Signaling pathways downstream of gp130 activation were also dissected. Numbers of A6(+ve) liver progenitor oval cells (LPCs) in CDE-treated murine liver were detected by immunohistochemistry and quantified. Levels of oval cell migration and proliferation were compared in CDE-treated mouse strains that depict models of gp130-mediated hyperactive ERK-1/2 signaling (gp130(deltaSTAT)), hyperactive STAT-3 signaling (gp130(Y757F) and Socs-3(-/deltaAlb)) or active ERK-1/2 as well as active STAT-3 signaling (wild-type). The A6(+ve) LPC numbers were increased with IL-6 treatment in vivo. The gp130(Y757F) mice displayed increased A6(+ve) LPCs numbers compared with wild-type and gp130(deltaSTAT) mice. Numbers of A6(+ve) LPCs were also increased in the livers of CDE treated Socs-3(-/deltaAlb) mice compared with their control counterparts. Lastly, inhibition of ERK-1/2 activation in cultured oval cells increased hyper IL-6-induced cell growth. For the first time, we have dissected the gp130-mediated signaling pathways, which influence liver progenitor oval cell proliferation.


CONCLUSIONS
Hyperactive STAT-3 signaling results in enhanced oval cell numbers, whereas ERK-1/2 activation suppresses oval cell proliferation.
Yeoh
George C T
GC
UWA Centre for Medical Research, The Western Australian Institute for Medical Research, Perth, Australia.
Ernst
Matthias
M
Rose-John
Stefan
S
Akhurst
Barbara
B
Payne
Christine
C
Long
Sarah
S
Alexander
Warren
W
Croker
Ben
B
Grail
Dianne
D
Matthews
Vance B
VB
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
C494200:Il6st protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D048052:Mitogen-Activated Protein Kinase 3