Nuclear factor-κB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury

Oakley, Fiona, Mann, Jelena, Nailard, Sarah, Smart, David E., Mungalsingh, Narenda, Constandinou, Christothea, Ali, Shakir, Wilson, Susan J., Millward-Sadler, Harry, Iredale, John P. and Mann, Derek A. (2005) Nuclear factor-κB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. The American Journal of Pathology, 166 (3), 695-708. (doi:10.1016/S0002-9440(10)62291-2).

Abstract

In this study we addressed the role of the nuclear factor (NF)-κB1/p50 subunit in chronic injury of the liver by determining the inflammatory and fibrotic responses of nfκb1-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 nfκb1−/− mice developed more severe neutrophilic inflammation and fibrosis compared to nfκb1+/+ mice. This phenotype was associated with elevated hepatic expression of tumor necrosis factor (TNF)-α, 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-α. Hepatic stellate cells derived from nfκb1−/− mice expressed TNF-α promoter activity, mRNA, and protein. By contrast the expression of other NF-κB-responsive genes (ICAM1 and interleukin-6) was similar between nfκb1−/− and nfκb1+/+ cells. We provide experimental evidence that the inappropriate expression of TNF-α by nfκb1−/− cells is because of lack of a p50-dependent histone deacetylase 1 (HDAC1)-mediated repression of TNF-α gene transcription. Taken together these data indicate that the p50 NF-κB subunit plays a critical protective role in the injured liver by limiting the expression of TNF-α and its recruitment of inflammatory cells.

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Contributors

Author: Susan J. Wilson

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