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J. Cell Biol.,
Volume 143, Number 7, December 28, 1998 2057-2065
Differentially Modulate Cellular Sensitivity to TNF/LT-
Cytotoxicity in L929 Cells
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, B-9000 Ghent,
Belgium
Tumor necrosis factor (TNF) and lymphotoxin (LT) 
are structurally and functionally related
cytokines. We expressed the TNF and LT- genes in
murine fibrosarcoma L929r2 cells, which can be sensitized to TNF/LT--dependent necrosis by inhibitors of transcription or translation. Autocrine production of
murine TNF in L929r2 cells completely downmodulated the expression of the 55- and 75-kD TNF receptors, resulting in resistance to TNF/LT- cytotoxicity.
Partial downmodulation of the 55-kD receptor was observed in human TNF-producing L929r2 cells. In contrast, an unaltered TNF receptor expression was found
on LT- L929r2 transfectants. Hence, although similar
cytotoxic effects are induced by extracellularly administered TNF and LT-, endogenous expression of these
cytokines fundamentally differs in the way they modulate TNF receptor expression. Unlike LT-, secreted by
the classical pathway, TNF is first formed as a membrane-bound protein, which is responsible for receptor downmodulation. To explore whether the different
pathways for secretion of TNF and LT- explain this
difference, we examined the effect of membrane-bound
LT- expression. This was obtained by exchange of the
classical signal sequence of LT- for the membrane anchor of chicken hepatic lectin. Membrane retention of
LT- resulted indeed in receptor downmodulation and
TNF/LT- resistance. We conclude that membrane retention of newly synthesized TNF or LT- is absolutely
required for receptor downmodulation and TNF/LT- resistance.
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