Effects of amino and imino acridines on tumor necrosis factor production by human leukocytes

Tumor necrosis factor (TNF) is a multifunctional cytokine with diverse effects on different cells and tissues. The biological activity of TNF is described on the basis of its cytotoxic action in vivo and in vitro. Different acridines were systematically synthesized and their effects were tested on endotoxin and Staphylococcus aureus-induced TNF production by human leukocytes. 9-aminobutylacridine and 9-ethylaminoacridine totally abrogated the TNF production of leucocytes at a concentration of 3.5 microM, whereas 9-imino -10-butylacridine and 9-imino-10-ethylacridine exerted only a 50% inhibition in the same concentration. Derivatives designated as 9-amino-(2-dimethylamino-ethyl)-acridine and 9-imino-10-(2-dimethylamino-ethyl)-acridine in a concentration of 7 microM exerted only a 30% and a 10% inhibition respectively. A significant modulation of TNF production was not observed when other alkylated derivatives in this series were applied. The TNF-mediated cytotoxic effect of monocytes against WEHI cells was also reduced by the most effective compounds. The acridines did not interfere with the expression of CD 14 molecules on monocytes. The exact mechanism of the suppression of TNF synthesis by acridines remains to be elucidated, but might be useful in the screening and evaluation of their anticancer properties and antimalarial effects.