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

Author:

Chen Xi-Lin,Zhang Qiang,Zhao Ruozhi,Medford Russell M.

Abstract

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-α-induced MCP-1 gene expression, suggesting important roles of superoxide ([Formula: see text]) and H2O2 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-α-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-α-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for [Formula: see text] generation, with diphenylene iodonium suppressed TNF-α-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and [Formula: see text] generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-α-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-α-induced MCP-1 and NF-κB transcriptional activity. These data suggest that ROS such as superoxide and H2O2 derived from Rac1-activated NADPH oxidase mediate TNF-α-induced MCP-1 expression in endothelial cells.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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