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

George Yeoh, M. Ernst, S. Rose-John, B. Akhurst, C. Payne, S. Long, W. Alexander, B. Croker, D. Grail, Vance Matthews

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)486-494
JournalHepatology
Volume45
Issue number2
DOIs
Publication statusPublished - 2007

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Cell Movement
Stem Cells
Ethionine
Cell Proliferation
Choline
Liver
Interleukin-6
Cell Count
Diet
Liver Regeneration
Knockout Mice
Cultured Cells
Immunohistochemistry
Wounds and Injuries
Growth

Cite this

Yeoh, George ; Ernst, M. ; Rose-John, S. ; Akhurst, B. ; Payne, C. ; Long, S. ; Alexander, W. ; Croker, B. ; Grail, D. ; Matthews, Vance. / Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation. In: Hepatology. 2007 ; Vol. 45, No. 2. pp. 486-494.
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title = "Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation",
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.",
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Yeoh, G, Ernst, M, Rose-John, S, Akhurst, B, Payne, C, Long, S, Alexander, W, Croker, B, Grail, D & Matthews, V 2007, 'Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation' Hepatology, vol. 45, no. 2, pp. 486-494. https://doi.org/10.1002/hep.21535

Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation. / Yeoh, George; Ernst, M.; Rose-John, S.; Akhurst, B.; Payne, C.; Long, S.; Alexander, W.; Croker, B.; Grail, D.; Matthews, Vance.

In: Hepatology, Vol. 45, No. 2, 2007, p. 486-494.

Research output: Contribution to journalArticle

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T1 - Opposing roles of gp130-mediated STAT-3 and ERK-1/2 signaling in liver progenitor cell migration and proliferation

AU - Yeoh, George

AU - Ernst, M.

AU - Rose-John, S.

AU - Akhurst, B.

AU - Payne, C.

AU - Long, S.

AU - Alexander, W.

AU - Croker, B.

AU - Grail, D.

AU - Matthews, Vance

PY - 2007

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N2 - 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.

AB - 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.

U2 - 10.1002/hep.21535

DO - 10.1002/hep.21535

M3 - Article

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JO - Hepatology

JF - Hepatology

SN - 0270-9139

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