Mannan binding lectin-associated serine protease 1 is induced by hepatitis C virus infection and activates human hepatic stellate cells

Authors

  • A. Saeed,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
    2. School of Pharmacy, University of Nottingham, Leicester, UK
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  • K. Baloch,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
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  • R. J. P. Brown,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
    Current affiliation:
    1. Division of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Medical School Hannover and Helmholtz Centre for Infection Research, Hannover, Germany
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  • R. Wallis,

    1. Departments of Infection, Immunity and Inflammation and Biochemistry, University of Leicester, Leicester, UK
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  • L. Chen,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
    2. School of Pharmacy, University of Nottingham, Leicester, UK
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  • L. Dexter,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
    2. School of Pharmacy, University of Nottingham, Leicester, UK
    Current affiliation:
    1. Microbiology Laboratory, University Hospital of Wales, Cardiff, UK
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  • C. P. McClure,

    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
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  • K. Shakesheff,

    1. School of Pharmacy, University of Nottingham, Leicester, UK
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  • B. J. Thomson

    Corresponding author
    1. School of Molecular Medical Sciences, University of Nottingham, Leicester, UK
    • Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals, Nottingham, UK
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Correspondence: B. J. Thomson, School of Molecular Medical Sciences and NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals, Nottingham NG7 2UH, UK.

E-mail: brian.thomson@nottingham.ac.uk

Summary

Mannan binding lectin (MBL)-associated serine protease type 1 (MASP-1) has a central role in the lectin pathway of complement activation and is required for the formation of C3 convertase. The activity of MASP-1 in the peripheral blood has been identified previously as a highly significant predictor of the severity of liver fibrosis in hepatitis C virus (HCV) infection, but not in liver disease of other aetiologies. In this study we tested the hypotheses that expression of MASP-1 may promote disease progression in HCV disease by direct activation of hepatic stellate cells (HSCs) and may additionally be up-regulated by HCV. In order to do so, we utilized a model for the maintenance of primary human HSC in the quiescent state by culture on basement membrane substrate prior to stimulation. In comparison to controls, recombinant MASP-1 stimulated quiescent human HSCs to differentiate to the activated state as assessed by both morphology and up-regulation of HSC activation markers α-smooth muscle actin and tissue inhibitor of metalloproteinase 1. Further, the expression of MASP-1 was up-regulated significantly by HCV infection in hepatocyte cell lines. These observations suggest a new role for MASP-1 and provide a possible mechanistic link between high levels of MASP-1 and the severity of disease in HCV infection. Taken together with previous clinical observations, our new findings suggest that the balance of MASP-1 activity may be proinflammatory and act to accelerate fibrosis progression in HCV liver disease.

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