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

Authors

  • George C. T. Yeoh,

    1. UWA Centre for Medical Research, The Western Australian Institute for Medical Research, Perth, Australia
    2. School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
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  • Matthias Ernst,

    1. Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia
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  • Stefan Rose-John,

    1. Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
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  • Barbara Akhurst,

    1. School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
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  • Christine Payne,

    1. UWA Centre for Medical Research, The Western Australian Institute for Medical Research, Perth, Australia
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  • Sarah Long,

    1. UWA Centre for Medical Research, The Western Australian Institute for Medical Research, Perth, Australia
    2. School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
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  • Warren Alexander,

    1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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  • Ben Croker,

    1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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  • Dianne Grail,

    1. Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia
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  • Vance B. Matthews

    Corresponding author
    1. UWA Centre for Medical Research, The Western Australian Institute for Medical Research, Perth, Australia
    2. School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
    3. Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia
    • Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia
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    • fax: (61) 3-8532-1100


  • Potential conflict of interest: Nothing to report.

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 (gp130ΔSTAT), hyperactive STAT-3 signaling (gp130Y757F and Socs-3−/ΔAlb) 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 gp130Y757F mice displayed increased A6+ve LPCs numbers compared with wild-type and gp130ΔSTAT mice. Numbers of A6+ve LPCs were also increased in the livers of CDE treated Socs-3−/ΔAlbmice 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. (HEPATOLOGY 2007;45:486–494.)

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