The c-Rel subunit of nuclear factor-κB regulates murine liver inflammation, wound-healing, and hepatocyte proliferation

Authors

  • Roben G. Gieling,

    Corresponding author
    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    • Liver Research Group, Institute of Cellular Medicine, 4th Floor, Cookson Building, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
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    • These authors contributed equally to the manuscript.

    • fax: +44-191-222-5455.

  • Ahmed M. Elsharkawy,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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    • These authors contributed equally to the manuscript.

    • A.M.E. was a Wellcome Trust Clinical Research Fellow.

  • Jorge H. Caamaño,

    1. Division of Immunity and Infection, Institute for BioMedical Research-Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom
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  • David E. Cowie,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Matthew C. Wright,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Mohammad R. Ebrahimkhani,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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    • M.R.E. was a European Association for the Study of the Liver (EASL) Dame Sheila Sherlock Fellow.

  • Alastair D. Burt,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Jelena Mann,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Pradip Raychaudhuri,

    1. Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL
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  • Hsiou-Chi Liou,

    1. Department of Immunology, Weill School of Medicine, Cornell University, New York, NY
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  • Fiona Oakley,

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Derek A. Mann

    1. Liver Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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  • Potential conflict of interest: Nothing to report.

Abstract

In this study, we determined the role of the nuclear factor-kappaB (NF-κB) subunit c-Rel in liver injury and regeneration. In response to toxic injury of the liver, c-Rel null (c-rel−/−) mice displayed a defect in the neutrophilic inflammatory response, associated with impaired induction of RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted; also known as CCL5). The subsequent fibrogenic/wound-healing response to both chronic carbon tetrachloride and bile duct ligation induced injury was also impaired and this was associated with deficiencies in the expression of fibrogenic genes, collagen I and α-smooth muscle actin, by hepatic stellate cells. We additionally report that c-Rel is required for the normal proliferative regeneration of hepatocytes in response to toxic injury and partial hepatectomy. Absence of c-Rel was associated with blunted and delayed induction of forkhead box M1 (FoxM1) and its downstream targets cyclin B1 and Cdc25C. Furthermore, isolated c-rel−/− hepatocytes expressed reduced levels of FoxM1 and a reduced rate of basal and epidermal growth factor–induced DNA synthesis. Chromatin immunoprecipitation revealed that c-Rel binding to the FoxM1 promoter is induced in the regenerating liver. Conclusion: c-Rel has multiple functions in the control of liver homeostasis and regeneration and is a transcriptional regulator of FoxM1 and compensatory hepatocyte proliferation. (HEPATOLOGY 2010.)

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