Nuclear factor-kappaB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury.
In this study we addressed the role of the nuclear factor (NF)-kappaB1/p50 subunit in chronic injury of the liver by determining the inflammatory and fibrotic responses of nfkappab1-null mice in an experimental model that mimics chronic liver disease. Mice received repeated hepatic injuries throughout 12 weeks by intraperitoneal injection of the hepatotoxin carbon tetrachloride. In response nfkappab1(-/-) mice developed more severe neutrophilic inflammation and fibrosis compared to nfkappab1(+/+) mice. This phenotype was associated with elevated hepatic expression of tumor necrosis factor (TNF)-alpha, which was localized to regions of the liver associated with inflammation and fibrosis. Hepatic stellate cells are important regulators of hepatic inflammatory and fibrogenic events but normally do not express TNF-alpha. Hepatic stellate cells derived from nfkappab1(-/-) mice expressed TNF-alpha promoter activity, mRNA, and protein. By contrast the expression of other NF-kappaB-responsive genes (ICAM1 and interleukin-6) was similar between nfkappab1(-/-) and nfkappab1(+/+) cells. We provide experimental evidence that the inappropriate expression of TNF-alpha by nfkappab1(-/-) cells is because of lack of a p50-dependent histone deacetylase 1 (HDAC1)-mediated repression of TNF-alpha gene transcription. Taken together these data indicate that the p50 NF-kappaB subunit plays a critical protective role in the injured liver by limiting the expression of TNF-alpha and its recruitment of inflammatory cells.
Oakley
Fiona
F
Liver Group, Southampton General Hospital, Southampton SO16 6YD UK.
Mann
Jelena
J
Nailard
Sarah
S
Smart
David E
DE
Mungalsingh
Narendra
N
Constandinou
Christothea
C
Ali
Shakir
S
Wilson
Susan J
SJ
Millward-Sadler
Harry
H
Iredale
John P
JP
Mann
Derek A
DA
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism; D005355:Fibrosis; D017930:Genes, Reporter; D005838:Genotype; D006655:Histone Deacetylases / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit; D009504:Neutrophils / Q000276:immunology; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000276:immunology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014945:Wound Healing
D052002:NF-kappa B p50 Subunit; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D012313:RNA; D005340:Fibrinogen; D002251:Carbon Tetrachloride; D006655:Histone Deacetylases
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