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J. Biol. Chem., Vol. 262, Issue 21, 10000-10007, 07, 1987
BB Aggarwal and TE Eessalu
We have investigated the effects of various interferons on the receptors
for recombinant tumor necrosis factor-alpha (rTNF-alpha) and also their
effects on rTNF-alpha-mediated cytotoxicity on human cervical carcinoma
cell line ME-180. Preincubation of cells with interferon (IFN)-gamma causes
a concentration- and time-dependent increase in rTNF-alpha receptor number
without any change in the affinity constant of the receptors. The increase
in receptor number is caused only by IFN-gamma and not by IFN-alpha or
IFN-beta. Approximately 4-6 h of preincubation with IFN-gamma are required
for maximum increase in rTNF-alpha binding to the cells, and this increase
can be abolished by inhibitors of protein synthesis, suggesting de novo
synthesis of rTNF-alpha receptors. The half-life of both uninduced and
induced receptors of rTNF-alpha is approximately 2 h, indicating a rapid
turnover. The binding of rTNF-alpha to the cells can also be eliminated by
pretreatment of cells with trypsin. Following the removal of trypsin,
binding of rTNF-alpha gradually increases, and this requires the synthesis
of new proteins. The cytotoxic effect of rTNF- alpha on ME-180 cells is
potentiated severalfold by the addition of either IFN-alpha, -beta, or
-gamma. However, at similar concentrations, relatively higher potentiation
of rTNF-alpha cytotoxicity is observed with IFN-gamma as compared to
IFN-alpha and IFN-beta. The pre-exposure of cells to IFNs is as effective
as co-exposure in enhancing cytotoxic effects of TNF-alpha. The induction
of TNF-alpha receptors by IFNs is observed in different cell types
regardless of their sensitivity to TNF- alpha, suggesting that increase in
receptor number alone is not sufficient for the enhanced cytotoxic
response. Because the enhancement of cytotoxic effects of TNF-alpha is
observed by all IFNs but receptor induction in ME-180 cells occurs only
with INF-gamma and because metabolic inhibitors which down-regulate
TNF-alpha receptors also enhance cytotoxic response, we suggest that the
induction of TNF-alpha receptor by IFNs is not a major mechanism of
synergism between these cytokines.
Induction of receptors for tumor necrosis factor-alpha by interferons is not a major mechanism for their synergistic cytotoxic response
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