Toll-like receptor 3 signaling attenuates liver regeneration

Authors

  • Elina Zorde-Khvalevsky,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Rinat Abramovitch,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
    2. MRI/MRS Laboratory, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Hila Barash,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
    2. MRI/MRS Laboratory, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Irit Spivak-Pohis,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Ludmila Rivkin,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Jacob Rachmilewitz,

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Eithan Galun,

    Corresponding author
    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
    • Goldyne Savad Institute for Gene Therapy, HBRC Hadassah–Hebrew University Medical Center, Jerusalem, 91120 Israel
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    • fax: (972)-2-6430982

  • Hilla Giladi

    1. Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah–Hebrew University Medical Center, Jerusalem, Israel
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  • Potential conflict of interest: Nothing to report.

Abstract

The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor κB (NF-κB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-β), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-κB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3wt and TLR3−/− mice. We found that following partial hepatectomy, TLR3−/− mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-κB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome. Conclusion: TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration. (HEPATOLOGY 2009.)

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