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Opposing roles of gp130‐mediated STAT‐3 and ERK‐1/2 signaling in liver progenitor cell migration and proliferation
Author(s) -
Yeoh George C. T.,
Ernst Matthias,
RoseJohn Stefan,
Akhurst Barbara,
Payne Christine,
Long Sarah,
Alexander Warren,
Croker Ben,
Grail Dianne,
Matthews Vance B.
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21535
Subject(s) - progenitor cell , mapk/erk pathway , glycoprotein 130 , cell growth , signal transduction , biology , microbiology and biotechnology , in vivo , endocrinology , medicine , cancer research , stat3 , stem cell , biochemistry
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 ΔSTAT ), hyperactive STAT‐3 signaling (gp130 Y757F 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 gp130 Y757F mice displayed increased A6 +ve LPCs numbers compared with wild‐type and gp130 ΔSTAT mice. Numbers of A6 +ve LPCs were also increased in the livers of CDE treated Socs‐3 −/ΔAlb 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. (H EPATOLOGY 2007;45:486–494.)