Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity

Authors

  • Hua Wang,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Ogyi Park,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Fouad Lafdil,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Kezhen Shen,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Norio Horiguchi,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Shi Yin,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Xin-Yuan Fu,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
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  • George Kunos,

    1. Section on Neuroendocrinology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
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  • Bin Gao

    Corresponding author
    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD
    • Section on Liver Biology, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892
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    • telephone: 301-443-3998. fax: 301-480-0257


  • Potential conflict of interest: Nothing to report.

Abstract

Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (HEPATOLOGY 2010.)

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