A study of the role of cytokines in the development of atherosclerosis using double knockout mice

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Atherosclerosis is a complex disease that is characterized by cholesterol deposition and monocyte infiltration into the subendothelial space. Proinflammatory cytokines, such as tumor necrosis factor-α(TNF-α), have been shown to be expressed in human atherosclerotic lesions, particularly in association with infiltrating monocytes and macrophages. TNF-α is thought to have important effects on the various cell types that are components of atherosclerotic lesions. Although considerable evidence regarding the functions of TNF-α has been accumulated in in vitro studies, their precise roles in the development of vascular lesions in bivo have not been established.The present study was conducted to examine the role of endogenous TNF-α in atherosclerosis. We used mice with a targeted disruption of TNF-αgene(TNF-α^<-1->), and crossed TNF-α^<-1-> mice with apoE^<-1-> mice, an animal model for atherosclerosis.The present study using apoE^<-1-> and apoE^<-1->/TNF-α^<-1-> mice provided the direct evidence that TNF-α promotes atherosclerotic lesion. The expressions of ICAM-1 and MCP-1 were elevated in apoE^<-1-> mice compared with apoE^<-1->/TNF-α^<-1-> mice. The uptake of oxidized LDL was significantly larger in macrophages from apoE^<-1-> mice than those from apoE^<-1->/TNF-α^<-1-> mice and the expression level or SRA was significantly higher in macrophages from apoE^<-1-> mice than those from apoE^<-1->/ TNF-α^<-1-> mice. TNF-α contributes to the generation of atherosclerotic lesion without the change in serum lipid concentration in apoE^<-1-> mice.