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The NF-κB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes

Lookup NU author(s): Dr Ahmed Elsharkawy, Professor Fiona Oakley, Professor Derek Mann, Professor Jelena Mann

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Abstract

Background & Aims: The pro-inflammatory functions of NF-kappa B must be tightly regulated to prevent inappropriate tissue damage and remodelling caused by activated inflammatory and wound-healing cells. The p50 subunit of NF-kappa B is emerging as an important repressor of immune and inflammatory responses, but by mechanisms that are poorly defined. This study aims to delineate p50 target genes in activated hepatic stellate cells and to outline mechanisms utilised in their repression. Methods: Hepatic stellate cells were isolated from njkb1(p50)deficient or Wt mice and gene expression compared using microarray. Target genes were verified by qRT-PCR and p50-mediated HDAC-1 recruitment to the target genes demonstrated using chromatin immunoprecipitation. Results: We identify p50 as transcriptional repressor of multiple pro-inflammatory genes including Ccl2, Cxcl10, Gm-csf, and Mmp-13. These genes are over-expressed in nfkb1(p50)-deficient mice suffering from chronic hepatitis and in fibrogenic/inflammatory hepatic stellate cells isolated from nfkb1(-/-) liver. We identify Mmp-13 as a bona-fide target gene for p50 and demonstrate that p50 is required for recruitment of the transcriptional repressor histone deacetylase (HDAC)-1 to kappa B sites in the Mmp-13 promoter. Chromatin immunoprecipitations identified binding of HDAC-1 to specific regulatory regions of the Ccl2,Cxcl10, Gm-csf genes that contain predicted kappa B binding motifs. Recruitment of HDAC-1 to these genes was not observed in nficb1(-/-) cells suggesting a requirement for p50 in a manner similar to that described for Mmp-13. Conclusions: Recruitment of HDAC-1 to inflammatory genes provides a widespread mechanism to explain the immunosuppressive properties of p50. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Publication metadata

Author(s): Elsharkawy AM, Oakley F, Lin F, Packham G, Mann DA, Mann J

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2010

Volume: 53

Issue: 3

Pages: 519-527

Print publication date: 02/06/2010

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier BV

URL: http://dx.doi.org/10.1016/j.jhep.2010.03.025

DOI: 10.1016/j.jhep.2010.03.025


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