Gene and Protein Responses of Human Monocytes to Extracellular Cysteine Redox Potential

The redox potential of the major thiol/disulfide couple, cysteine (Cys) and its disulfide cystine (CySS), in plasma (E(h)Cys) is oxidized in association with oxidative stress, and oxidized E(h)Cys is associated with cardiovascular disease risk. In vitro exposure of monocytes to oxidized E(h)Cys increases expression of the proinflammatory cytokine, interleukin-1beta (IL-1beta), suggesting that E(h)Cys could be a mechanistic link between oxidative stress and chronic inflammation. Because cell membranes contain multiple Cys-rich proteins, which could be sensitive to E(h)Cys, we sought to determine whether E(h)Cys 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 E(h)Cys. Pathway analysis results revealed that in addition to IL-1beta-related pathways, components of stress/detoxification and cell death pathways were increased by oxidized E(h)Cys, 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 E(h) and that cell proliferation was stimulated with reduced E(h). Therefore, plasma E(h)Cys provides a control over monocyte phenotype, which could contribute to cardiovascular disease risk and provide a novel therapeutic target for disease prevention.