Role of Endogenous TNF-alpha and Sphingosine in Induced DNA Synthesis in Regenerating Rat Liver after Partial Hepatectomy

A. V. Alessenko^1*, L. V. Platonova², G. R. Sakevarashvili², A. V. Khrenov¹, L. N. Shingarova¹, N. I. Shono², and E. I. Galperin²

¹Institute of Biochemical Physics, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 117977 Russia; fax: (095) 137-4101

²Sechenov Moscow Medical Academy, ul. Bol'shaya Pirogovskaya 2/6, Moscow, 119435 Russia; fax: (095) 118-8238

^* To whom correspondence should be addressed.

Received November 3, 1998; Revision received February 24, 1999

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Cytokine-stimulated metabolism of sphingomyelin results in the accumulation of ceramide and sphingosine which play a part in the regulation of cell proliferation, differentiation, and reception, as well as in oncogenesis. Formation of TNF-alpha (a member of the cytokine family), accumulation of sphingosine, and DNA synthesis (measured by immunoblotting, HPLC, and [³H]thymidine incorporation, respectively) were studied in rat liver after partial hepatectomy. The content of TNF-alpha was found to increase during 12 h following hepatectomy. The maximum of sphingomyelinase activity and accumulation of sphingosine preceed the maximum of DNA synthesis. Sphingosine is known to inhibit protein kinase C. On the other hand, it stimulates the metabolism of phosphatidylinositol, thus causing accumulation of diacylglycerol and inositol-1,4,5-triphosphate, which in turn activate protein kinase C. Hence, the release of TNF-alpha in regenerating liver may modulate DNA synthesis through the accumulation of sphingosine which is involved in regulation of protein kinase C activity and of phosphatidylinositol turnover.

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KEY WORDS: TNF-alpha, sphingosine, sphingomyelinase, sphingomyelin cycle, hepatectomy, DNA synthesis, cell proliferation

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