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Inhibition of interferon production in human fibroblasts by a tumor promoting phorbol ester

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Summary

The effect of 12-0-tetradecanoylphorbol-13-acetate (TPA) on the induction of interferon in cultures of human fibroblasts was examined. TPA was found to inhibit polyinosinate-polycytidylate [poly(I) · poly(C)]-induced interferon production when added either before or with the inducer. A 3-hour pretreatment of FS-4 cells with TPA produced the greatest inhibitory effect. Partially inhibitory treatments with TPA caused a delay in interferon production. On the other hand, interferon yields were slightly enhanced by TPA added at 1 1/2 or 3 hours post-induction. No gross metabolic perturbations (e.g., inhibition of cellular protein or RNA synthesis) were detected which would explain the phenomenon. The inhibition of interferon production was a stereospecific event: biologically inactive derivatives of TPA (4-0-methyl TPA, 4-α-phorbol-12, 13-didecanoate and phorbol-12, 13-diacetate) had no effect on interferon production. Cellular proteases or nucleases did not appear to be involved in this process. The binding of labeled poly(I) · poly(C) to FS-4 cells was unaltered in TPA-treated cultures. In super-induced cultures (i.e., after enhancement of interferon yields by actinomycin D and cycloheximide), interferon production was generally less inhibited by TPA than after simple induction. Newcastle disease virus (NDV)-induced interferon synthesis in GM-258 cells was also inhibited by the phorbol ester. Both α (leukocyte) and β (fibroblast) interferon production was inhibited to a similar degree in TPA-treated cells inoculated with 0.1 or 1 plaque forming unit (PFU) of NDV per cell. Increasing the multiplicity of infection with NDV to 10 PFU per cell overcame the inhibitory action of TPA. We conclude that the site of TPA action is either the triggering (generation of the hypothetical inducing signal) or transcription of the interferon mRNA.

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  1. H. M. Frankfort

    Present address: Laboratory of Genetics, Rockefeller University, 1275 York Avenue, 10021, New York, NY, USA

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  1. Department of Microbiology, New York University School of Medicine, New York, USA

    H. M. Frankfort & J. Vilček

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Frankfort, H.M., Vilček, J. Inhibition of interferon production in human fibroblasts by a tumor promoting phorbol ester. Archives of Virology 73, 295–309 (1982). https://doi.org/10.1007/BF01318083

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