Lack of gp130 expression results in more bacterial infection and higher mortality during chronic cholestasis in mice

Authors

  • Torsten Wuestefeld,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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    • Dr. Wuestefeld and Dr. Klein both contributed equally to this work.

  • Christian Klein,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Medizinische Klinik III, University Hospital Aachen, RWTH Aachen, Germany
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    • Dr. Wuestefeld and Dr. Klein both contributed equally to this work.

  • Konrad L. Streetz,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Medizinische Klinik III, University Hospital Aachen, RWTH Aachen, Germany
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  • Naiara Beraza,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Medizinische Klinik III, University Hospital Aachen, RWTH Aachen, Germany
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  • Jürgen Schölmerich,

    1. Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
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  • Lawrence J. Burgart,

    1. Mayo Clinic College of Medicine, Rochester, MN
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  • Lars Zender,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Stefan Kubicka,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Gregory J. Gores,

    1. Mayo Clinic College of Medicine, Rochester, MN
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Christian Trautwein

    Corresponding author
    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Medizinische Klinik III, University Hospital Aachen, RWTH Aachen, Germany
    • Medical Clinic III, University Hospital of Aachen, Pauwelsstrasse D-52074 Aachen, 30, Germany
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    • fax: 49-241-80-82455


  • Potential conflict of interest: Nothing to report.

Abstract

Chronic cholestasis is associated with increased bacterial infections and sepsis resulting in higher mortality in humans. In the current study, we investigated the relevance of gp130-dependent pathways after bile duct ligation (BDL). BDL was performed in conditional gp130 knockout (loxP/Cre system) mice and respective controls. Liver injury, regulation of the acute phase response, and the impact on survival and bacterial infections were determined. Acute BDL resulted in increased IL-6 levels, Stat3 activation, and an increase in acute-phase proteins (serum-amyloid-A [SAA]), which was blocked in gp130-deleted animals. In addition, the antimicrobial gene hepcidin was regulated in a gp130-dependent manner after BDL. During chronic cholestasis Stat3 activation was dramatically reduced, while high SAA levels were maintained via gp130-dependent signaling. Inhibition of gp130-dependent pathways resulted in higher mortality and liver damage, which was associated with higher infiltration of immune-activated cells and increased germ number in the liver. In conclusion, during acute and chronic cholestasis, the gp130 system is essential for controlling the acute-phase response. Lack of gp130 expression results in pronounced bacterial growth in bile and liver after BDL, which is associated with higher mortality. Activation of gp130-dependent pathways after BDL is essential and appears to be a therapeutic target during cholestasis. (HEPATOLOGY 2005;42:1082–1090.)

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