RESISTANCE TO TUMOR-NECROSIS-FACTOR (TNF) CYTOTOXICITY BY AUTOCRINE TNF PRODUCTION IS INDEPENDENT OF INTRACELLULAR SIGNALING PATHWAYS

We previously showed that autocrine tumor necrosis factor (TNF) produc tion in the TNF-sensitive L929sA fibrosarcoma cell line induced TNF re sistance, which is correlated with downmodulation of both TNF receptor s on the cell surface, We now analysed whether autocrine TNF productio n also interfered with intracellular TNF signaling pathways, The L929s A-CAT-R55i cell line, in which cell death can be induced by controlled cytoplasmic expression of a trimeric fusion protein between chloramph enicol acetyltransferase and the intracellular domain of TNF-R55 (CAT- R55i), was supertransfected with the murine TNF gene, Expression of th e latter conferred resistance to cell death induced by exogenous TNF, while cytotoxicity induced by CAT-R55i was not impaired. This demonstr ates that autocrine TNF did not induce intracellular mechanisms that b lock TNF signaling leading to cell death. Thus the induction of TNF re sistance via autocrine TNF production in L929sA cells is solely due to downmodulation of TNF receptors on the cell surface. (C) 1997 Federat ion of European Biochemical Societies.