ToxSci Advance Access originally published online on September 11, 2009
Toxicological Sciences 2009 112(2):354-362; doi:10.1093/toxsci/kfp205
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Gene and Protein Responses of Human Monocytes to Extracellular Cysteine Redox Potential
* Division of Pulmonary, Allergy and Critical Care Medicine
BioMolecular Computing Resource, Department of Medicine, Emory University, Atlanta, Georgia 30322
3 To whom correspondence should be addressed at Emory University, 205 Whitehead Research Center, Atlanta, GA 30322. Fax: (404) 712-2974. E-mail: dpjones{at}emory.edu.
Received May 25, 2009; accepted August 21, 2009
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Abstract |
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The redox potential of the major thiol/disulfide couple, cysteine (Cys) and its disulfide cystine (CySS), in plasma (EhCys) is oxidized in association with oxidative stress, and oxidized EhCys is associated with cardiovascular disease risk. In vitro exposure of monocytes to oxidized EhCys increases expression of the proinflammatory cytokine, interleukin-1β (IL-1β), suggesting that EhCys could be a mechanistic link between oxidative stress and chronic inflammation. Because cell membranes contain multiple Cys-rich proteins, which could be sensitive to EhCys, we sought to determine whether EhCys specifically affects proinflammatory signaling or has other effects on monocytes. We used microarray analysis and mass spectrometry–based proteomics to evaluate global changes in protein redox state, gene expression, and protein abundance in monocytes in response to EhCys. Pathway analysis results revealed that in addition to IL-1β-related pathways, components of stress/detoxification and cell death pathways were increased by oxidized EhCys, while components of cell growth and proliferation pathways were increased by a reduced potential. Phenotypic studies confirmed that a cell stress response occurred with oxidized Eh and that cell proliferation was stimulated with reduced Eh. Therefore, plasma EhCys provides a control over monocyte phenotype, which could contribute to cardiovascular disease risk and provide a novel therapeutic target for disease prevention.
Key Words: gene expression array; oxidative stress; pathway analysis; plasma redox potential; proteomics; mass spectrometry based.
1 These authors contributed equally to this study.
2 Present address: Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655.