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(American Journal of Pathology. 2005;166:695-708.)
© 2005 American Society for Investigative Pathology

Nuclear Factor-{kappa}B1 (p50) Limits the Inflammatory and Fibrogenic Responses to Chronic Injury

Fiona Oakley*, Jelena Mann*, Sarah Nailard*, David E. Smart*, Narendra Mungalsingh*, Christothea Constandinou*, Shakir Ali{dagger}, Susan J. Wilson{ddagger}, Harry Millward-Sadler*, John P. Iredale* and Derek A. Mann*

From the Liver Group* and Respiratory Cell and Molecular Biology,{ddagger} Division of Infection, Inflammation, and Repair, University of Southampton, Southampton General Hospital, Southampton, United Kingdom; and Jamia Hamdard University,{dagger} New Delhi, India

In this study we addressed the role of the nuclear factor (NF)-{kappa}B1/p50 subunit in chronic injury of the liver by determining the inflammatory and fibrotic responses of nf{kappa}b1-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 nf{kappa}b1–/– mice developed more severe neutrophilic inflammation and fibrosis compared to nf{kappa}b1+/+ 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 nf{kappa}b1–/– mice expressed TNF-{alpha} promoter activity, mRNA, and protein. By contrast the expression of other NF-{kappa}B-responsive genes (ICAM1 and interleukin-6) was similar between nf{kappa}b1–/– and nf{kappa}b1+/+ cells. We provide experimental evidence that the inappropriate expression of TNF-{alpha} by nf{kappa}b1–/– 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-{kappa}B subunit plays a critical protective role in the injured liver by limiting the expression of TNF-{alpha} and its recruitment of inflammatory cells.




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