Study of the Signal Transduction of and Cellular Response (Growth Stimulation and Cytotoxicity) to Tumor Necrosis Factor

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Tumor Necrosis Factor (TNF) exerts cytotoxic and cytostatic action against certain tumor cells while sparing normal cells both in vitro and in vivo. TNF is thought to have both growth stimulatory and inhibitory signals. We discovered that human diploid fibroblast FS-4 cells, which growth was stimulated by TNF, generated prostaglandin that suppressed cell growth. By the analysis of prostaglandins, PGE_2 was the main prostaglandin produced in FS-4 cells and the production of this prostaglandin was stimulated by TNF-treatment. Furthermore, when prostaglandin production was enhanced by the addition of arachidonate, TNF acts as cytotoxic factor against FS-4 cells. For elucidating the early event of TNF-signal transduction, TNF receptor was purified by TNF-affinity chromatograpy was examined. TNF receptor was a molecular assembly of 300 kDa, including G-protein. Therefore, TNF-signal might stimulate phospholipase A_2 via G-protein, then released arachidonate might convert to prostaglandins. Next, the involvement of prostaglandins in the cytotoxic action of TNF was examined using TNF-sensitive L929 cells and TNF-resistant sublines. L929 cells generated prostaglandin by the treatment of TNF, whereas TNF-resistant sublines did not. Furthermore the cytotoxic action of TNF on L929 cells was inhibited by the addition of indomethacin, suggesting that prostaglandin may be involved in the cytotoxic action of TNF. These results indicate the involvement of prostaglandinproducing pathway in the cytotoxic action of TNF.