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  • Title: Induction of receptors for tumor necrosis factor-alpha by interferons is not a major mechanism for their synergistic cytotoxic response.
    Author: Aggarwal BB, Eessalu TE.
    Journal: J Biol Chem; 1987 Jul 25; 262(21):10000-7. PubMed ID: 2440858.
    Abstract:
    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.
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