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© The Rockefeller University Press,
0021-9525/1998//2057 $5.00
The Journal of Cell Biology, Volume 143, Number 7,
, 1998 2057-2065
Regular Articles |
Autocrine Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) 
Differentially Modulate Cellular Sensitivity to TNF/LT- Cytotoxicity in L929 Cells
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.
Key Words: tumor necrosis factor • lymphotoxin • cytotoxicity • downmodulation • membrane
Abbreviations used in this paper: ActD, actinomycin D; CHL, chicken hepatic lectin; CHX, cycloheximide; hLT, human lymphotoxin; hTNF, human TNF; IL, interleukin; LT, lymphotoxin; mIFN, murine interferon; mTNF, murine TNF; neor, neomycin-resistant; TNF, tumor necrosis factor; TNF-R55, 55-kD TNF receptor; TNF-R75, 75-kD TNF receptor.
S. Cornelis and B. Vanhaesebroeck are postdoctoral researchers with the Fonds voor Wetenschappelijk Onderzoek—Vlaanderen. Research was supported by the Interuniversitaire Attractiepolen and the Vlaams Actiecomité voor Biotechnologie.
Dr. Vanhaesebroeck's present address is Ludwig Institute for Cancer Research, London W1P 8BT, UK.
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