Inhibitory effects of TNFα on mouse tumor Leydig cells:: possible role of ceramide in the mechanism of action

TNF alpha is reported to inhibit steroidogenesis in mouse Leydig cells. In primary cells this inhibition resulted mainly from a reduced expression of Cyp-17 gene. Mouse tumor Leydig cells, MA-IO, being free of macrophages and lacking Cyp-17, appear to be an excellent model to investigate those effects of TNFa which are independent of either macrophages or Cyp-17. We report here that TNF alpha receptors are expressed in this cell line. Treatment of the cells with TNF alpha had no effect on basal progesterone production. In contrast, LH-, 8Br-cAMP and forskolin-stimulated progesterone production was inhibited by TNF alpha. Neither enzymes involved in the conversion of cholesterol to pregnenolone nor hormone-induced hydrolysis of [C-14] cholesterol-ester were affected by TNF alpha. The hormone- induced expression of StAR protein was diminished in mitochondrial fractions from TNF alpha-treated cells. Also cell permeable ceramides markedly inhibited StAR protein levels. We show further that TNF alpha was able to induce [C-14]-ceramide accumulation in MA-10 cells and suggest that this sphingolipid may be considered as a transmitter of TNF alpha signals to the StAR protein. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.