Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation

Yeoh, GCT; Ernst, M; Rose-John, S; Akhurst, B; Payne, C; Long, S; Alexander, W; Croker, B; Grail, D; Matthews, VB

Author(s): Yeoh, GCT; Ernst, M; Rose-John, S; Akhurst, B; Payne, C; Long, S; Alexander, W; Croker, B; Grail, D; Matthews, VB;
Details: Publication Year 2007-02,Volume 45,Issue #2,Page 486-494
Journal Title: HEPATOLOGY
Publication Type: Journal Article
Abstract: 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(Delta STAT)), hyperactive STAT-3 signaling (gp130(Y757F) and Socs-3(-/Delta Alb)) 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(Delta STAT) mice. Numbers of A6(+ve) LPCs were also increased in the livers of CDE treated Socs-3(-/Delta Alb) 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. Conclusion: Hyperactive STAT-3 signaling results in enhanced oval cell numbers, whereas ERK-1/2 activation suppresses oval cell proliferation.
Publisher: JOHN WILEY & SONS INC
Keywords: ACUTE-PHASE RESPONSE; GP130 MUTANT MICE; OVAL CELLS; HEPATOCELLULAR-CARCINOMA; DESIGNER CYTOKINE; GENE ACTIVATION; IN-VIVO; KAPPA-B; REGENERATION; EXPRESSION
Publisher's Version: https://doi.org/10.1002/hep.21535
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2007-02-01 12:00:00