Peroxide-mediated chromatin remodelling of a nuclear factor kappa B site in the mouse inducible nitric oxide synthase promoter.

Published

Journal Article

Hepatocyte expression of iNOS (inducible nitric oxide synthase) and synthesis of nitric oxide convey protective antioxidant functions in models of sepsis, shock and reperfusion. However, the underlying redox-sensitive mechanisms that regulate hepatocyte expression of iNOS and its antioxidant functions are largely unknown. Activity of the transcription factor NF-kappaB (nuclear factor kappaB) is known to be redox-modulated. In this regard, the mouse hepatocyte iNOS promoter has NF-kappaB-binding sites at nt -1044 to -1034 and at nt -114 to -104, which are considered to be critical for iNOS expression in response to pro-inflammatory cytokine stimulation. The relative contribution of these two NF-kappaB-binding sites in the mouse iNOS promoter to hepatocyte iNOS promoter activity in the context of oxidative stress has not been characterized previously. In addition, although the cis - and trans -regulatory factors controlling mouse hepatocyte iNOS expression have been well-characterized, the local changes in chromatin structure that accompany activation of iNOS gene transcription have not been considered. In the present study, we demonstrate that (1) in the absence of exogenous oxidative stress, the NF-kappaB site at nt -114 is inactive and (2) peroxide-mediated oxidative stress induces hyperacetylation and enhanced accessibility of the restriction enzyme to this NF-kappaB region. Our results suggest that chromatin structural changes activate this NF-kappaB site and increase interleukin-1beta-stimulated iNOS expression in the presence of oxidative stress.

Full Text

Duke Authors

Cited Authors

  • Wei, J; Guo, H; Gao, C; Kuo, PC

Published Date

  • February 1, 2004

Published In

Volume / Issue

  • 377 / Pt 3

Start / End Page

  • 809 - 818

PubMed ID

  • 14599292

Pubmed Central ID

  • 14599292

Electronic International Standard Serial Number (EISSN)

  • 1470-8728

Digital Object Identifier (DOI)

  • 10.1042/BJ20031235

Language

  • eng

Conference Location

  • England