Keratins 8 and 18 are type II acute-phase responsive genes overexpressed in human liver disease

Authors

  • Nurdan Guldiken,

    1. Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
    2. IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
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    • Both authors contributed equally to this work.
  • Valentyn Usachov,

    1. Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
    2. IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
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    • Both authors contributed equally to this work.
  • Kateryna Levada,

    1. Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
    2. IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
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  • Christian Trautwein,

    1. IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
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  • Marianne Ziol,

    1. Pathology Department, GH Paris-Seine-Saint-Denis, APHP, Bondy, France
    2. University Paris 13, Bobigny, France
    3. Centre de Ressources Biologiques – Hôpital Jean Verdier, GH Paris-Seine-Saint-Denis, APHP, Bondy, France
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  • Pierre Nahon,

    1. Pathology Department, GH Paris-Seine-Saint-Denis, APHP, Bondy, France
    2. University Paris 13, Bobigny, France
    3. Department of Hepatology, APHP, Jean Verdier Hospital, Bondy, France
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  • Pavel Strnad

    Corresponding author
    1. IZKF and Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany
    • Correspondence

      Pavel Strnad, Department of Internal Medicine III and IZKF, University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany

      Tel: +49 241 80-35324

      Fax: +49 241 80-82455

      e-mail: pstrnad@ukaachen.de

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Abstract

Background & Aims

Keratins (Ks) 7, 8, 18 and 19 constitute important markers and modifiers of liver disease. In mice, K8 and K18 are stress inducible and a dysregulated K8 > K18 stoichiometry predisposes to formation of Mallory–Denk bodies (MDBs), i.e. aggregates characteristic of chronic liver disorders such as alcoholic liver disease (ALD). In our study, we analyse the expression and the regulation of keratins in context of human liver disease.

Methods

K7, K8, K18 and K19 mRNA levels were determined in liver biopsies from patients with ALD, non-alcoholic steatohepatitis (NASH), chronic hepatitis B (HBV), hepatitis C (HCV) and from control subjects. HepG2 and Hep3B cells were treated with IL-1β, IL-6 and TNF-α. Mice were injected with turpentine, an established IL-6 inducer.

Results

K7, K8 and K18 were 1.5- to 3-fold upregulated in livers of ALD and HCV patients with a more active disease, but not in HBV/NASH subjects, while K19 was significantly elevated in all analysed disorders. K8 and K18 expression displayed a strong correlation (r = 0.89), but dysregulated levels with the K8 > K18 state were seen in ALD. All keratins were overexpressed in subjects with moderate vs. minimal inflammation, while K7, K8 and K18 were upregulated in patients with advanced liver fibrosis. In HepG2/Hep3B cells, IL-6 treatment but not IL-1β or TNF-α significantly increased K8 and K18 expression and elevated K18 levels were seen after turpentine injection.

Conclusions

Keratins represent type II acute-phase responsive genes overexpressed in specific human liver disorders. A K8 > K18 state occurs in ALD and predisposes to MDB formation.

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