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The c-Rel Subunit of Nuclear Factor-κB Regulates Murine Liver Inflammation, Wound-Healing, and Hepatocyte Proliferation

Lookup NU author(s): Dr Roben Gieling, Dr Ahmed Elsharkawy, Dr David Cowie, Professor Matthew Wright, Dr Mohammed Ebrahimkhani, Professor Alastair Burt, Professor Jelena Mann, Professor Fiona Oakley, Professor Derek Mann

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Abstract

In this study, we determined the role of the nuclear factor-kappaB (NF-kappa B) 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 alpha-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;51:922-931.)


Publication metadata

Author(s): Gieling RG, Elsharkawy AM, Caamano JH, Cowie DE, Wright MC, Ebrahimkhani MR, Burt AD, Mann J, Raychaudhuri P, Liou HC, Oakley F, Mann DA

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2010

Volume: 51

Issue: 3

Pages: 922-931

Print publication date: 01/03/2010

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/hep.23385

DOI: 10.1002/hep.23385


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