Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase-1 expression and up-regulates matrix metalloproteinase-9 in toxic liver injury

Authors

  • Martin Roderfeld,

    1. Department of Gastroenterology (Medical Clinic 11), University Hospital, Justus-Liebig-University, Giessen, Germany,
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    • *These two authors contributed equally to this study.

  • Andreas Geier,

    1. Department of Gastroenterology and Hepatology (Medical Clinic III), University Hospital, Aachen University (RWTH), Aachen, Germany
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    • *These two authors contributed equally to this study.

  • Christoph G. Dietrich,

    1. Department of Gastroenterology and Hepatology (Medical Clinic III), University Hospital, Aachen University (RWTH), Aachen, Germany
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  • Elmar Siewert,

    1. Department of Gastroenterology and Hepatology (Medical Clinic III), University Hospital, Aachen University (RWTH), Aachen, Germany
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  • Bettina Jansen,

    1. Department of Gastroenterology and Hepatology (Medical Clinic III), University Hospital, Aachen University (RWTH), Aachen, Germany
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  • Carsten Gartung,

    1. Department of Gastroenterology and Hepatology (Medical Clinic III), University Hospital, Aachen University (RWTH), Aachen, Germany
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  • Elke Roeb

    1. Department of Gastroenterology (Medical Clinic 11), University Hospital, Justus-Liebig-University, Giessen, Germany,
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Elke Roeb, MD, Department of Gastroenterology (Medical Clinic II), University Hospital, Justus-Liebig-University Giessen, Paul-Meimberg-Str. 5, D-35385 Giessen, Germany.
Tel: +49 641 99 42337
Fax: +49 641 99 42339
e-mail: elke.roeb@innere.med.uni-giessen.de

Abstract

Abstract: Background: Tissue inhibitor of metalloproteinases (TIMP)-1, the most important endogenous inhibitor of matrix metalloproteinases, plays a pivotal role in the pathogenesis of liver fibrosis and may represent an effective therapeutic target in the design of antifibrotic strategies for chronic liver diseases.

Methods: Intraperitoneal application of a single dose of either tumor necrosis factor (TNF)-α or interleukin (IL)-1β in mice led to an enhanced expression of hepatic TIMP-1 after 4–16 h. Male Sprague–Dawley rats were treated with carbon tetrachloride (CCl4) in the presence and absence of specific TNF-α and IL-1β inhibitors.

Results: Real-time PCR revealed a significant increase of TIMP-1 mRNA in total rat liver 24 h after CCl4 injection. Repetitive injection of both, etanercept and anakinra, before and after CCl4 injection effectively inactivated TNF-α and IL-1β. Anticytokine pretreatment reduced the increase of TIMP-1 expression after a single CCl4 injection by 50% and 75%, respectively. In contrast to CCl4-treated rats with and without TNF-α blockade, IL-1β inactivation caused a sevenfold increase in matrix metalloproteinases-9 mRNA levels.

Conclusions: In conclusion, TIMP-1 expression is up-regulated in the early phase of toxic liver injury by proinflammatory cytokines such as TNF-α and IL-1β in rodents. Pharmacological inactivation of these cytokines significantly reduces TIMP-1 gene expression. Our data provide a potential new antifibrotic approach.

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