EFFECT OF TUMOR-NECROSIS-FACTOR ON FREE SPHINGOSINE CONTENT AND SPHINGOMYELINASE ACTIVITY IN MURINE LIVER-CELLS AND NUCLEI

The activity of sphingomyelinase and the content of free sphingosine i n liver cells and cell nuclei have been studied in C57bl mice followin g administration of recombinant human tumor necrosis factor (TNF) at 1 0 or 40 mg/kg body weight. Sphingomyelinase is the key enzyme of sphin gomyelin metabolism, and sphingosine, a product of extensive enzymatic hydrolysis of sphingomyelin, can regulate the activity of various pho sphokinases. We have shown that murine cells initially respond to TNF by inhibition of the enzyme activity; the activation becomes evident o nly al a more prolonged residence time of the factor in animals (2 and 4 h with 10 and 40 mg/kg, respectively). The activation of sphingomye linase in the nuclei is observed within the first 60 min after TNF adm inistration. Sphingosine accumulation in liver cells and cell nuclei c oincides with sphingomyelinase activation. Activation of the sphingomy elin cycle induced by TNF is an early response, more pronounced in the nuclei as compared to whole cells. It is suggested that TNF signal tr ansduction involves phosphorylation of TNF receptors by a sphingosine- dependent mechanism.