NF-kappa B is a critical regulator of the survival of rodent and human hepatic myofibroblasts

Martha R. Watson, Karen Wallace, Roben G. Gieling, Derek M. Manas, Ellis Jaffray, Ronald T. Hay, Derek A. Mann, Fiona Oakley

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    Abstract

    Background/Aims: Hepatic myofibroblast activation during injury causes deposition of extracellular matrix within the liver and promotes development of fibrosis. Hepatic myofibroblast apoptosis is associated with remodelling of fibrotic extracellular matrix and regression of fibrosis. Previous work showed that inhibition of constitutive NF-kappa B signaling promotes hepatic myofibroblast apoptosis and resolution of fibrosis in rodent models. However, to date agents used to target constitutive NF-kappa B transcriptional activity in hepatic myofibroblasts have been relatively non-specific with potential for off-target effects that may complicate data interpretation. Likewise, rat chronic liver disease models may not accurately recapitulate the activation of human hepatic myofibroblasts.

    Methods: We used a mutant recombinant IKB alpha super-repressor fused to the HIV-TAT domain to specifically target NF-kappa B signaling in hepatic myofibroblasts. Inhibition of NF-kappa B activity was measured using reporter assay. Apoptosis of hepatic myofibroblasts was assessed by morphological changes, cleavage of the PARP-I protein and Caspase 3 activation.

    Results: TAT-I kappa B alpha SR reduced NF-kappa B dependent transcription, Bcl-2 expression and promoted Jun-N-terminal kinase-dependent apoptosis in human and rat hepatic myofibroblasts.

    Conclusions: These data highlight the conserved role of NF-kappa B during fibrogenesis. Our data validate the use of rodent models for pre-clinical testing of NF-kappa B inhibitors as anti-fibrotics and stimulators of fibrotic extracellular matrix remodelling. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

    Original languageEnglish
    Pages (from-to)589-597
    Number of pages9
    JournalJournal of Hepatology
    Volume48
    Issue number4
    DOIs
    Publication statusPublished - Apr 2008

    Keywords

    • NF-kappa B (NF-kappaB)
    • hepatic myofibroblast
    • liver fibrosis
    • apoptosis
    • STELLATE CELL APOPTOSIS
    • RAT-LIVER FIBROSIS
    • AUTOIMMUNE HEPATITIS
    • GENE-EXPRESSION
    • IKK-ALPHA
    • INHIBITION
    • ACTIVATION
    • REVERSIBILITY
    • FIBROGENESIS
    • RESOLUTION

    Cite this

    Watson, M. R., Wallace, K., Gieling, R. G., Manas, D. M., Jaffray, E., Hay, R. T., Mann, D. A., & Oakley, F. (2008). NF-kappa B is a critical regulator of the survival of rodent and human hepatic myofibroblasts. Journal of Hepatology, 48(4), 589-597. https://doi.org/10.1016/j.jhep.2007.12.019