Production of two distinct and independent hepatic immunoregulatory molecules by the perfused rat liver

Authors

  • Francis V. Chisari M.D.,

    Corresponding author
    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
    • Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, California 92037
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  • Mary Nakamura,

    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
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  • David R. Milich,

    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
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  • Keith Han,

    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
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  • Daniel Molden,

    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
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  • Geert G. Leroux-Roels

    1. Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; Yale Medical School, New Haven, Connecticut
    2. Associated Pathologists, Las Vegas, Nevada; and Department of Internal Medicine, Medical School, State University of Ghent, Ghent, Belgium
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Abstract

By manipulating dietary sugar intake and perfusate glucose concentration, we have identified two independent hepatic immunoregulatory molecules produced by the perfused rat liver. The first is released by injured hepatocytes, appears in perfusates together with hepatocellular glutamic pyruvic transaminase, is quantitatively inhibited by exogenous L-arginine and coelutes with arginase on high-pressure liquid chromatography. Based on these findings, we conclude that this activity is due to the release of cytoplasmic arginase from injured hepatocytes. Since supplementation studies reveal that lymphocyte proliferation is exquisitely arginine-dependent, it is conceivable that arginase released by injured hepatocytes might influence lymphocyte function in vivo by local arginine depletion. The second immunoregulatory molecule is released by noninjured hepatocytes following induction by sugar, particularly glucose, both in vivo or in vitro. This inducible activity is arginase-independent, triglyceride-rich and floats at a density less than 1.006 gm per ml upon ultracentrifugation. Based on these characteristics, we tentatively ascribe this activity to hepatic very low density lipoprotein, the serum counterpart of which is known to express many immunoregulatory properties. These results directly illustrate for the first time the pathophysiological conditions required for the secretion and release of these distinct and independent hepatic immunoregulatory molecules, and they suggest possible routes by which they may influence immunological homeostasis and immunologically mediated liver disease.

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