14576080

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3

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.

eng

IM

MEDLINE

0363-6135

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H1001-7

pubmed-meshheading:14576080-Antineoplastic Agents, pubmed-meshheading:14576080-Aorta, pubmed-meshheading:14576080-Catalase, pubmed-meshheading:14576080-Cells, Cultured, pubmed-meshheading:14576080-Chemokine CCL2, pubmed-meshheading:14576080-Dimethyl Sulfoxide, pubmed-meshheading:14576080-Endothelium, Vascular, pubmed-meshheading:14576080-Free Radical Scavengers, pubmed-meshheading:14576080-Gene Expression, pubmed-meshheading:14576080-Humans, pubmed-meshheading:14576080-Hydrogen Peroxide, pubmed-meshheading:14576080-Hydroxides, pubmed-meshheading:14576080-Iron, pubmed-meshheading:14576080-Iron Chelating Agents, pubmed-meshheading:14576080-Metalloporphyrins, pubmed-meshheading:14576080-NADPH Oxidase, pubmed-meshheading:14576080-NF-kappa B, pubmed-meshheading:14576080-Promoter Regions, Genetic, pubmed-meshheading:14576080-Pyridones, pubmed-meshheading:14576080-RNA, Messenger, pubmed-meshheading:14576080-Signal Transduction, pubmed-meshheading:14576080-Superoxide Dismutase, pubmed-meshheading:14576080-Superoxides, pubmed-meshheading:14576080-Thiourea, pubmed-meshheading:14576080-Tumor Necrosis Factor-alpha, pubmed-meshheading:14576080-rac1 GTP-Binding Protein

Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't