Insulin up-regulates tumor necrosis factor-alpha production in macrophagesthrough an extracellular-regulated kinase-dependent pathway

Hyperinsulinemia has recently been reported as a risk factor for atheroscle rotic diseases such as coronary heart disease; however, the effect of insul in on the development of atherosclerosis is not well understood. Here we ha ve investigated the direct effect of insulin on macrophages, which are know n to be important in the atherosclerotic process. We treated THP-1 macropha ges with insulin (10(-7) M) and examined the gene expression using nucleic acid array systems. The results of array analysis showed that insulin stimu lated gene expression of tumor necrosis factor-alpha (TNF-alpha) the most a mong all genes in the analysis. In addition, insulin administration to macr ophages enhanced both mRNA expression and protein secretion of TNF-alpha in a dose-dependent manner. To determine the signaling pathway involved in th is TNF-alpha response to insulin, we pretreated. the cells with three disti nct protein kinase inhibitors: wortmannin, PD98059, and SB203580. Only PD98 059, which inhibits extracellular signal-regulated kinases, suppressed insu lin-induced production of TNF-alpha mRNA and protein in THP-1 macrophages. These observations indicate that insulin stimulates TNF-alpha production in macrophages by regulating the expression of TNF-alpha mRNA and that the ex tracellular signal-regulated kinase signaling pathway may have a critical r ole in stimulating the production of TNF-alpha in response to insulin in ma crophages.