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

RG Gieling, AM Elsharkawy, Jorge Caamano, DE Cowie, MC Wright, MR Ebrahimkhani, AD Burt, J Mann, P Raychaudhuri

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

In this study, we determined the role of the nuclear factor-kappaB (NF-kappaB) 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.
Original languageEnglish
Pages (from-to)922-31
Number of pages10
JournalHepatology
Volume51
Issue number3
DOIs
Publication statusPublished - 1 Mar 2010

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