The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis

F. Oakley, M. Meso, J. P. Iredale, X. Zhou, M. J. May, H. Milward-Sadler, Matthew Christopher Wright, D. A. Mann

    Research output: Contribution to journalArticle

    214 Citations (Scopus)

    Abstract

    Background& Aims: Resolution of liver fibrosis is associated with clearance of hepatic myofibroblasts by apoptosis; development of strategies that promote this process in a selective way is therefore important. The aim of this study was to determine whether the inhibitor of kappaB kinase suppresser sulfasalazine stimulates hepatic myofibroblast apoptosis and recovery from fibrosis. Methods: Hepatic myofibroblasts were generated by culture activation of rat and human hepatic stellate cells. Fibrosis was established in rat livers by chronic injury with carbon tetrachloride followed by recovery with or without sulfasalazine (150 mg/kg) treatment. Results: Treatment of hepatic stellate cells with sulfasalazine (0.5-2.0 mmol/L) induced apoptosis of activated rat and human hepatic stellate cells. A single in vivo administration of sulfasalazine promoted accelerated recovery from fibrosis as assessed by improved fibrosis score, selective clearance of smooth muscle alpha-actin-positive myofibroblasts, reduced hepatic procollagen I and tissue inhibitor of metalloproteinase 1 messenger RNA expression, and increased matrix metalloproteinase 2 activity. Mechanistic studies showed that sulfasalazine selectively blocks nuclear factor-kappaB- dependent gene transcription, inhibits hepatic stellate cell expression of Gadd45beta, stimulates phosphorylation of Jun N-terminal kinase 2, and promotes apoptosis by a mechanism that is prevented by the Jun N-terminal kinase inhibitor SP600125. As further evidence for a survival role for the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway in activated hepatic stellate cells, a highly selective cell-permeable peptide inhibitor Of kappaB kinase activation also stimulated hepatic stellate cell apoptosis via a Jun N-terminal kinase- dependent mechanism. Conclusions: Inhibition of the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway is sufficient to increase the rate at which activated hepatic stellate cells undergo apoptosis both in vitro and in vivo, and drugs that selectively target inhibitor Of kappaB kinase have potential as antifibrotics.

    Original languageEnglish
    Pages (from-to)108-120
    Number of pages12
    JournalGastroenterology
    Volume128
    Issue number1
    DOIs
    Publication statusPublished - 2005

    Keywords

    • MITOCHONDRIAL PERMEABILITY TRANSITION
    • MEDIATED APOPTOSIS
    • TISSUE INHIBITOR
    • P65 SUBUNIT
    • SULFASALAZINE
    • ACTIVATION
    • EXPRESSION
    • ALPHA
    • PHOSPHORYLATION
    • CIRRHOSIS

    Cite this

    The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis. / Oakley, F.; Meso, M.; Iredale, J. P.; Zhou, X.; May, M. J.; Milward-Sadler, H.; Wright, Matthew Christopher; Mann, D. A.

    In: Gastroenterology, Vol. 128, No. 1, 2005, p. 108-120.

    Research output: Contribution to journalArticle

    Oakley, F, Meso, M, Iredale, JP, Zhou, X, May, MJ, Milward-Sadler, H, Wright, MC & Mann, DA 2005, 'The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis', Gastroenterology, vol. 128, no. 1, pp. 108-120. https://doi.org/10.1053/j.gastro.2004.10.003
    Oakley, F. ; Meso, M. ; Iredale, J. P. ; Zhou, X. ; May, M. J. ; Milward-Sadler, H. ; Wright, Matthew Christopher ; Mann, D. A. / The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis. In: Gastroenterology. 2005 ; Vol. 128, No. 1. pp. 108-120.
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    title = "The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis",
    abstract = "Background& Aims: Resolution of liver fibrosis is associated with clearance of hepatic myofibroblasts by apoptosis; development of strategies that promote this process in a selective way is therefore important. The aim of this study was to determine whether the inhibitor of kappaB kinase suppresser sulfasalazine stimulates hepatic myofibroblast apoptosis and recovery from fibrosis. Methods: Hepatic myofibroblasts were generated by culture activation of rat and human hepatic stellate cells. Fibrosis was established in rat livers by chronic injury with carbon tetrachloride followed by recovery with or without sulfasalazine (150 mg/kg) treatment. Results: Treatment of hepatic stellate cells with sulfasalazine (0.5-2.0 mmol/L) induced apoptosis of activated rat and human hepatic stellate cells. A single in vivo administration of sulfasalazine promoted accelerated recovery from fibrosis as assessed by improved fibrosis score, selective clearance of smooth muscle alpha-actin-positive myofibroblasts, reduced hepatic procollagen I and tissue inhibitor of metalloproteinase 1 messenger RNA expression, and increased matrix metalloproteinase 2 activity. Mechanistic studies showed that sulfasalazine selectively blocks nuclear factor-kappaB- dependent gene transcription, inhibits hepatic stellate cell expression of Gadd45beta, stimulates phosphorylation of Jun N-terminal kinase 2, and promotes apoptosis by a mechanism that is prevented by the Jun N-terminal kinase inhibitor SP600125. As further evidence for a survival role for the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway in activated hepatic stellate cells, a highly selective cell-permeable peptide inhibitor Of kappaB kinase activation also stimulated hepatic stellate cell apoptosis via a Jun N-terminal kinase- dependent mechanism. Conclusions: Inhibition of the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway is sufficient to increase the rate at which activated hepatic stellate cells undergo apoptosis both in vitro and in vivo, and drugs that selectively target inhibitor Of kappaB kinase have potential as antifibrotics.",
    keywords = "MITOCHONDRIAL PERMEABILITY TRANSITION, MEDIATED APOPTOSIS, TISSUE INHIBITOR, P65 SUBUNIT, SULFASALAZINE, ACTIVATION, EXPRESSION, ALPHA, PHOSPHORYLATION, CIRRHOSIS",
    author = "F. Oakley and M. Meso and Iredale, {J. P.} and X. Zhou and May, {M. J.} and H. Milward-Sadler and Wright, {Matthew Christopher} and Mann, {D. A.}",
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    TY - JOUR

    T1 - The IKK inhibitor sulfasalazine stimulates JNK-dependent hepatic stellate cell apoptosis and accelerates recovery from rat liver fibrosis

    AU - Oakley, F.

    AU - Meso, M.

    AU - Iredale, J. P.

    AU - Zhou, X.

    AU - May, M. J.

    AU - Milward-Sadler, H.

    AU - Wright, Matthew Christopher

    AU - Mann, D. A.

    PY - 2005

    Y1 - 2005

    N2 - Background& Aims: Resolution of liver fibrosis is associated with clearance of hepatic myofibroblasts by apoptosis; development of strategies that promote this process in a selective way is therefore important. The aim of this study was to determine whether the inhibitor of kappaB kinase suppresser sulfasalazine stimulates hepatic myofibroblast apoptosis and recovery from fibrosis. Methods: Hepatic myofibroblasts were generated by culture activation of rat and human hepatic stellate cells. Fibrosis was established in rat livers by chronic injury with carbon tetrachloride followed by recovery with or without sulfasalazine (150 mg/kg) treatment. Results: Treatment of hepatic stellate cells with sulfasalazine (0.5-2.0 mmol/L) induced apoptosis of activated rat and human hepatic stellate cells. A single in vivo administration of sulfasalazine promoted accelerated recovery from fibrosis as assessed by improved fibrosis score, selective clearance of smooth muscle alpha-actin-positive myofibroblasts, reduced hepatic procollagen I and tissue inhibitor of metalloproteinase 1 messenger RNA expression, and increased matrix metalloproteinase 2 activity. Mechanistic studies showed that sulfasalazine selectively blocks nuclear factor-kappaB- dependent gene transcription, inhibits hepatic stellate cell expression of Gadd45beta, stimulates phosphorylation of Jun N-terminal kinase 2, and promotes apoptosis by a mechanism that is prevented by the Jun N-terminal kinase inhibitor SP600125. As further evidence for a survival role for the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway in activated hepatic stellate cells, a highly selective cell-permeable peptide inhibitor Of kappaB kinase activation also stimulated hepatic stellate cell apoptosis via a Jun N-terminal kinase- dependent mechanism. Conclusions: Inhibition of the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway is sufficient to increase the rate at which activated hepatic stellate cells undergo apoptosis both in vitro and in vivo, and drugs that selectively target inhibitor Of kappaB kinase have potential as antifibrotics.

    AB - Background& Aims: Resolution of liver fibrosis is associated with clearance of hepatic myofibroblasts by apoptosis; development of strategies that promote this process in a selective way is therefore important. The aim of this study was to determine whether the inhibitor of kappaB kinase suppresser sulfasalazine stimulates hepatic myofibroblast apoptosis and recovery from fibrosis. Methods: Hepatic myofibroblasts were generated by culture activation of rat and human hepatic stellate cells. Fibrosis was established in rat livers by chronic injury with carbon tetrachloride followed by recovery with or without sulfasalazine (150 mg/kg) treatment. Results: Treatment of hepatic stellate cells with sulfasalazine (0.5-2.0 mmol/L) induced apoptosis of activated rat and human hepatic stellate cells. A single in vivo administration of sulfasalazine promoted accelerated recovery from fibrosis as assessed by improved fibrosis score, selective clearance of smooth muscle alpha-actin-positive myofibroblasts, reduced hepatic procollagen I and tissue inhibitor of metalloproteinase 1 messenger RNA expression, and increased matrix metalloproteinase 2 activity. Mechanistic studies showed that sulfasalazine selectively blocks nuclear factor-kappaB- dependent gene transcription, inhibits hepatic stellate cell expression of Gadd45beta, stimulates phosphorylation of Jun N-terminal kinase 2, and promotes apoptosis by a mechanism that is prevented by the Jun N-terminal kinase inhibitor SP600125. As further evidence for a survival role for the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway in activated hepatic stellate cells, a highly selective cell-permeable peptide inhibitor Of kappaB kinase activation also stimulated hepatic stellate cell apoptosis via a Jun N-terminal kinase- dependent mechanism. Conclusions: Inhibition of the inhibitor Of kappaB kinase/nuclear factor-kappaB pathway is sufficient to increase the rate at which activated hepatic stellate cells undergo apoptosis both in vitro and in vivo, and drugs that selectively target inhibitor Of kappaB kinase have potential as antifibrotics.

    KW - MITOCHONDRIAL PERMEABILITY TRANSITION

    KW - MEDIATED APOPTOSIS

    KW - TISSUE INHIBITOR

    KW - P65 SUBUNIT

    KW - SULFASALAZINE

    KW - ACTIVATION

    KW - EXPRESSION

    KW - ALPHA

    KW - PHOSPHORYLATION

    KW - CIRRHOSIS

    U2 - 10.1053/j.gastro.2004.10.003

    DO - 10.1053/j.gastro.2004.10.003

    M3 - Article

    VL - 128

    SP - 108

    EP - 120

    JO - Gastroenterology

    JF - Gastroenterology

    SN - 0016-5085

    IS - 1

    ER -