Tumor necrosis factor (TNF) secreted by macrophages in response to external invasive stimuli has cytolytic and cytostatic effects on transformed, but not on normal cells. However, treatment of whole animals or cancer patients with TNF causes, in addition to tumor necrosis, a number of pathophysiological conditions. These conditions include inhibition of lipid synthesis and depletion of lipid reserves. It is proposed that the complex effects of TNF in whole animals or humans may be due to a common mechanism of TNF action on the promoters of different genes. In this study, fully differentiated adipocytes, TA-1 cells, and recombinant human TNF will be used to examine how, and at what level of the gene expression of acetyl CoA carboxylase (ACC), TNF exerts its effects. ACC is the rate-limiting enzyme for long chain fatty acid biogenesis, and the synthesis of this enzyme is inhibited by TNF. For the examination of TNF action on the promoter, the ACC promoter will be ligated to the bacterial chloramphenicol acetyl transferase gene, and the chimeric gene will be transfected into TA-1 cells in which the TNF effect on the bacterial gene can be examined. Eventually, the trans-acting factor mediating TNF will be isolated and its effect on other promoters will be examined.
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