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

Roben G. Gieling, Ahmed M. Elsharkawy, Jorge H. Caamã No, David E. Cowie, Matthew C. Wright, Mohammad Ebrahimkhani, Alastair D. Burt, Jelena Mann, Pradip Raychaudhuri, Hsiou Chi Liou, Fiona Oakley, Derek A. Mann

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

In this study, we determined the role of the nuclear factor-kappaB (NF-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-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.

Original languageEnglish (US)
Pages (from-to)922-931
Number of pages10
JournalHepatology
Volume51
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

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Wound Healing
Hepatocytes
Inflammation
Liver Regeneration
Poisons
Liver
Wounds and Injuries
Cyclin B1
Chemokine CCL5
Hepatic Stellate Cells
Carbon Tetrachloride
Chromatin Immunoprecipitation
Hepatectomy
Bile Ducts
Epidermal Growth Factor
Ligation
Smooth Muscle
Actins
Regeneration
Homeostasis

ASJC Scopus subject areas

  • Hepatology

Cite this

Gieling, R. G., Elsharkawy, A. M., Caamã No, J. H., Cowie, D. E., Wright, M. C., Ebrahimkhani, M., ... Mann, D. A. (2010). The c-rel subunit of nuclear factor-κb regulates murine liver inflammation, wound-healing, and hepatocyte proliferation. Hepatology, 51(3), 922-931. https://doi.org/10.1002/hep.23385

The c-rel subunit of nuclear factor-κb regulates murine liver inflammation, wound-healing, and hepatocyte proliferation. / Gieling, Roben G.; Elsharkawy, Ahmed M.; Caamã No, Jorge H.; Cowie, David E.; Wright, Matthew C.; Ebrahimkhani, Mohammad; Burt, Alastair D.; Mann, Jelena; Raychaudhuri, Pradip; Liou, Hsiou Chi; Oakley, Fiona; Mann, Derek A.

In: Hepatology, Vol. 51, No. 3, 03.2010, p. 922-931.

Research output: Contribution to journalArticle

Gieling, RG, Elsharkawy, AM, Caamã No, JH, Cowie, DE, Wright, MC, Ebrahimkhani, M, Burt, AD, Mann, J, Raychaudhuri, P, Liou, HC, Oakley, F & Mann, DA 2010, 'The c-rel subunit of nuclear factor-κb regulates murine liver inflammation, wound-healing, and hepatocyte proliferation', Hepatology, vol. 51, no. 3, pp. 922-931. https://doi.org/10.1002/hep.23385
Gieling, Roben G. ; Elsharkawy, Ahmed M. ; Caamã No, Jorge H. ; Cowie, David E. ; Wright, Matthew C. ; Ebrahimkhani, Mohammad ; Burt, Alastair D. ; Mann, Jelena ; Raychaudhuri, Pradip ; Liou, Hsiou Chi ; Oakley, Fiona ; Mann, Derek A. / The c-rel subunit of nuclear factor-κb regulates murine liver inflammation, wound-healing, and hepatocyte proliferation. In: Hepatology. 2010 ; Vol. 51, No. 3. pp. 922-931.
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AU - Wright, Matthew C.

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AU - Burt, Alastair D.

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