The c-Rel subunit of nuclear factor-kappaB regulates murine liver inflammation, wound-healing, and hepatocyte proliferation.
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.
Gieling
Roben G
RG
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
Elsharkawy
Ahmed M
AM
Caamaño
Jorge H
JH
Cowie
David E
DE
Wright
Matthew C
MC
Ebrahimkhani
Mohammad R
MR
Burt
Alastair D
AD
Mann
Jelena
J
Raychaudhuri
Pradip
P
Liou
Hsiou-Chi
HC
Oakley
Fiona
F
Mann
Derek A
DA
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*
D016328:NF-kappa B