title: The c-Rel subunit of nuclear factor-kappaB regulates murine liver inflammation, wound-healing, and hepatocyte proliferation.
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.
  
  
  CONCLUSIONS
  c-Rel has multiple functions in the control of liver homeostasis and regeneration and is a transcriptional regulator of FoxM1 and compensatory hepatocyte proliferation.
authors.affiliation: Liver Research Group, Institute of Cellular Medicine, 4th Floor, Cookson Building, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom. roben.gieling@ncl.ac.uk
authors.forename: Roben G
authors.initials: RG
authors.lastname: Gieling
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elsharkawy
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Caamaño
authors.forename: David E
authors.initials: DE
authors.lastname: Cowie
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wright
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ebrahimkhani
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006505:Hepatitis / Q000209:etiology*; D022781:Hepatocytes / Q000166:cytology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D016328:NF-kappa B