Increased toxin-induced liver injury and fibrosis in interleukin-6–deficient mice

Authors

  • Kellen Kovalovich,

    1. Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA
    2. Department of Medicine, University of Pennsylvania Medical School, Philadelphia, PA
    3. Division of Gastroenterology, University of Pennsylvania Medical School, Philadelphia, PA
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  • Robert A. DeAngelis,

    1. Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA
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  • Wei Li,

    1. Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA
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  • Emma E. Furth,

    1. Department of Medicine, University of Pennsylvania Medical School, Philadelphia, PA
    2. Department of Pathology, University of Pennsylvania Medical School, Philadelphia, PA
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  • Gennaro Ciliberto,

    1. Istituto Ricerce di Biologia Molecolare (IRBM), Rome, Italy
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  • Dr. Rebecca Taub

    Corresponding author
    1. Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA
    • 705A Stellar-Chance, 422 Curie Boulevard, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. fax: (215) 573-2195
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Abstract

Interleukin-6 null (IL-6−/−) mice have impaired liver regeneration and increased liver necrosis following partial hepatectomy that is corrected with IL-6 treatment. Following acute carbon tetrachloride (CCl4 ) treatment, we found that IL-6−/− mice developed increased hepatocellular injury and defective regeneration with significant blunting of signal transducer-and-activator of transcription protein 3 (STAT3) and nuclear factor-κB (NF-κB) activation and reduced hepatocyte DNA synthetic and mitotic responses. After CCl4 treatment, unlike partial hepatectomy, increased hepatocyte apoptosis was noted in IL-6−/− livers. Pretreatment with IL-6 before CCl4 reduced acute CCl4 injury and apoptosis and accelerated regeneration in both IL-6+/+ and −/− livers. Repetitive doses of CCl4 in the presence or absence of phenobarbital resulted in increased injury and fibrosis in IL-6 −/− compared with +/+ livers. After acute and chronic injury, IL-6−/− livers showed the protracted presence of α-smooth muscle actin associated with activated stellate cells, indicating a disturbed response in wound healing that progressed to fibrosis. These data provide evidence for an important role for IL-6 in reducing CCl4 –induced acute and chronic liver injury and fibrosis.

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