Role of endogenous TNF-alpha and sphingosine in induced DNA synthesis in regenerating rat liver after partial hepatectomy

Cytokine-stimulated metabolism of sphingomyelin results in the accumulation of ceramide and sphingosine which play a part in the regulation of cell pr oliferation, differentiation, and reception, as well as in oncogenesis. For mation of TNF-alpha (a member of the cytokine family), accumulation of sphi ngosine, and DNA synthesis (measured by immunoblotting, HPLC, and [H-3]thym idine incorporation, respectively) were studied in rat liver after partial hepatectomy. The content of TNF-alpha was found to increase during 12 h fol lowing hepatectomy. The maximum of sphingomyelinase activity and accumulati on of sphingosine preceed the maximum of DNA synthesis. Sphingosine is know n to inhibit protein kinase C. On the other hand, it stimulates the metabol ism of phosphatidylinositol, thus causing accumulation of diacylglycerol an d inositol-1,4,5-triphosphate, which in turn activate protein kinase C. Hen ce, the release of TNF-a in regenerating liver may modulate DNA synthesis t hrough the accumulation of sphingosine which is involved in regulation of p rotein kinase C activity and of phosphatidylinositol turnover.