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Oxidative stress and TNF-a induce histone Acetylation and NF-кB/AP-1 activation in Alveolar epithelial cells: Potential mechanism In gene transcription in lung inflammation

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Oxygen/Nitrogen Radicals: Cell Injury and Disease

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 37))

Abstract

Oxidants and inflammatory mediators such as tumour necrosis factor-a (TNF-a) activate nuclear factor kappa B (NF-KB) and activator protein-1 (AP-1) transcription factors, and enhance the expression of both pro-inflammatory and protective antioxidant genes. Remodelling of chromatin within the nucleus, controlled by the degree of acetylation/deacetylation of histone residues on the histone core around which DNA is coiled, is important in allowing access for transcription factor DNA binding and hence gene transcription. Unwinding of DNA is important in allowing access for transcription factor DNA binding and hence gene transcription. Nuclear histone acetylation is a reversible process, and is regulated by a group of acetyltransferases (HATs) which promote acetylation, and deacetylases (HDACs) which promote deacetylation. The aim of this study was to determine whether oxidative stress and the pro-inflammatory mediator, TNF-a, altered histone acetylation/deacetylation and the activation of NF-KB andAP-1, leading to the release of the pro-inflammatory cytokine IL-8 in human alveolar epithelial cells (A549). Hydrogen peroxide (H202) (100)cM) and TNF-a (10 ng/ml) imposed oxidative stress in A549 cells as shown by depletion of the antioxidant reduced glutathione (GSH) concomitant with increased levels of oxidised glutathione (GSSG). Treatment of A549 cells with H»2TNF-a and the HDAC inhibitor, trichostatin A, TSA (100 ng/ml) significantly increased acetylation of histone proteins shown by immunostaining of cells and increased HAT activity, compared to the untreated cells. H202and TNF-a, and TSA all increased NF-KB and AP-1 DNA binding to their consensus sites assessed by the electrophoretic mobility shift assay. TSA treatment potentiated the increased AP-1 and NF-KB binding, produced by H»2or TNF-a treatments in A549 cells. Both H202and TNF-a significantly increased IL-8 release, which was further enhanced by pre-treatment of A549 cells with TSA compared to the individual treatments. This study shows that the oxidant H202and the pro-inflammatory mediator, TNF-a induce histone acetylation which is associated with decreased GSH levels and increased AP-1 and NF-KB activation leading to enhanced proinflammatory IL-8 release in alveolar epithelial cells. This indicates a mechanism for the pro-inflammatory effects of oxidative stress. (Mol Cell Biochem 234/235: 239–248, 2002)

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Authors and Affiliations

  1. ELEGI Colt Research Laboratory, Respiratory Medicine Unit, University of Edinburgh, Medical School, Edinburgh, UK

    Irfan Rahman, Peter S. Gilmour, Luis Albert Jimenez & William MacNee

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  1. Irfan Rahman
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  2. Peter S. Gilmour
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  3. Luis Albert Jimenez
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  4. William MacNee
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Editors and Affiliations

  1. Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road Mall Stop B167, Morgantown, WV, 26505, USA

    Val Vallyathan , Xianglin Shi Ph.D.  & Vince Castranova ,  & 

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Rahman, I., Gilmour, P.S., Jimenez, L.A., MacNee, W. (2002). Oxidative stress and TNF-a induce histone Acetylation and NF-кB/AP-1 activation in Alveolar epithelial cells: Potential mechanism In gene transcription in lung inflammation. In: Vallyathan, V., Shi, X., Castranova, V. (eds) Oxygen/Nitrogen Radicals: Cell Injury and Disease. Developments in Molecular and Cellular Biochemistry, vol 37. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1087-1_28

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  • DOI: https://doi.org/10.1007/978-1-4615-1087-1_28

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5388-1

  • Online ISBN: 978-1-4615-1087-1

  • eBook Packages: Springer Book Archive

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