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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1972 Jul;69(7):1851–1854. doi: 10.1073/pnas.69.7.1851

Increased Susceptibility of Cells Treated with Interferon to the Toxicity of Polyriboinosinic·Polyribocytidylic Acid

William E Stewart II 1, Erik De Clercq 1, Alfons Billiau 1, Jan Desmyter 1, Pierre De Somer 1
PMCID: PMC426817  PMID: 4505664

Abstract

Concentrations of the synthetic polymer polyriboinosinic·polyribocytidylic acid that produced no detectable toxicity in normal L cells produced marked cytotoxicity in L cells treated with interferon. This increase in the susceptibility of cells to the toxicity of the polymer was also observed in human cells and secondary mouse embryo cells treated with homologous interferons before exposure to the polynucleotides. The degree of enhancement of toxicity was dependent on the concentration of interferon to which the cells were exposed. The ratio of antiviral activity induced by interferon to enhancement of toxicity by interferon remained constant through about 1000-fold purification. Various interferon preparations induced by viruses or by polyriboinosinic·polyribocytidylic acid in vivo or in vitro, and international reference standard interferons all exhibited enhancement of toxicity. Both enhancement of toxicity and antiviral activity were destroyed by trypsin and by incubation at 56° for 1 hr, did not act on heterologous cells, were not sedimented by ultracentrifugation, and were not inactivated by ribonuclease, deoxyribonuclease, irradiation with ultraviolet light, or exposure to a pH of 2.

Keywords: L cells, mouse embryo cells, human embryonic skin fibroblasts, VSV, NDV

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baugh C. L., Tytell A. A., Hilleman M. R. In vitro safety assessment of double-stranded polynucleotides poly I:C and Mu-9. Proc Soc Exp Biol Med. 1971 Sep;137(4):1194–1198. doi: 10.3181/00379727-137-35754. [DOI] [PubMed] [Google Scholar]
  2. Bialy H. S., Colby C. Inhibition of early vaccinia virus ribonucleic acid synthesis in interferon-treated chicken embryo fibroblasts. J Virol. 1972 Feb;9(2):286–289. doi: 10.1128/jvi.9.2.286-289.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. CDe Clercq E., Eckstein F., Sternbach H., Merigan T. C. The antiviral activity of thiophosphate-substituted polyribonucleotides in vitro and in vivo. Virology. 1970 Oct;42(2):421–428. doi: 10.1016/0042-6822(70)90285-0. [DOI] [PubMed] [Google Scholar]
  4. Cordell-Stewart B., Taylor M. W. Effect of double-stranded viral RNA on mammalian cells in culture. Proc Natl Acad Sci U S A. 1971 Jun;68(6):1326–1330. doi: 10.1073/pnas.68.6.1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Clercq E., Wells R. D., Grant R. C., Merigan T. C. Thermal activation of the antiviral activity of synthetic double-stranded polyribonucleotides. J Mol Biol. 1971 Feb 28;56(1):83–100. doi: 10.1016/0022-2836(71)90086-6. [DOI] [PubMed] [Google Scholar]
  6. Dianzani F., Cantagalli P., Gagnoni S., Rita G. Effect of DEAE-dextran on production of interferon induced by synthetic double-stranded RNA in L cell cultures. Proc Soc Exp Biol Med. 1968 Jul;128(3):708–710. doi: 10.3181/00379727-128-33105. [DOI] [PubMed] [Google Scholar]
  7. Fontaine-Brouty-Boyé D., Gresser I., Macieira-Coelho A., Rosenfeld C., Thomas M. T. Inhibition in vitro de la mulitplication des cellules leucémiques murines L 1210 oar des prparations d'interféron. C R Acad Sci Hebd Seances Acad Sci D. 1969;269(3):406–408. [PubMed] [Google Scholar]
  8. Gresser I., Brouty-Boyé D., Thomas M. T., Macieira-Coelho A. Interferon and cell division. I. Inhibition of the multiplication of mouse leukemia L 1210 cells in vitro by interferon preparations. Proc Natl Acad Sci U S A. 1970 Aug;66(4):1052–1058. doi: 10.1073/pnas.66.4.1052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gresser I., Brouty-Boyé D., Thomas M. T., Macieira-Coelho A. Interferon and cell division. II. Influence of various experimental conditions on the inhibition of L1210 cell multiplication in vitro by interferon preparations. J Natl Cancer Inst. 1970 Dec;45(6):1145–1153. [PubMed] [Google Scholar]
  10. Gresser I., Thomas M. T., Brouty-Boyé D., Macieira-Coelho A. Interferon and cell division. V. Titration of the anticellular action of interferon preparations. Proc Soc Exp Biol Med. 1971 Sep;137(4):1258–1261. doi: 10.3181/00379727-137-35768. [DOI] [PubMed] [Google Scholar]
  11. Hilleman M. R. Prospects for the use of double-stranded ribonucleic acid (poly I:C) inducers in man. J Infect Dis. 1970 Feb;121(2):196–211. doi: 10.1093/infdis/121.2.196. [DOI] [PubMed] [Google Scholar]
  12. Horak I., Jungwirth C., Bodo G. Poxvirus specific cytopathic effect in interferon-treated L cells. Virology. 1971 Aug;45(2):456–462. doi: 10.1016/0042-6822(71)90345-x. [DOI] [PubMed] [Google Scholar]
  13. Huang K. Y., Landay M. E. Enhancement of the lethal effects of endotoxins by interferon inducers. J Bacteriol. 1969 Nov;100(2):1110–1111. doi: 10.1128/jb.100.2.1110-1111.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hugh R., Huang K. Y., Elliott T. B. Enhancement of bacterial infections in mice by newcastle disease virus. Infect Immun. 1971 Mar;3(3):488–493. doi: 10.1128/iai.3.3.488-493.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Joklik W. K., Merigan T. C. Concerning the mechanism of action of interferon. Proc Natl Acad Sci U S A. 1966 Aug;56(2):558–565. doi: 10.1073/pnas.56.2.558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lindahl-Magnusson P., Leary P., Gresser I. Interferon and cell division. VI. Inhibitory effect of interferon on the multiplication of mouse embryo and mouse kidney cells in primary cultures. Proc Soc Exp Biol Med. 1971 Dec;138(3):1044–1050. doi: 10.3181/00379727-138-36047. [DOI] [PubMed] [Google Scholar]
  17. Macieira-Coelho A., Brouty-Boyé D., Thomas M. T., Gresser I. Interferon and cell division. 3. Effect of interferon on the division cycle of L1210 cells in vitro. J Cell Biol. 1971 Feb;48(2):415–419. doi: 10.1083/jcb.48.2.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Marcus P. I., Engelhardt D. L., Hunt J. M., Sekellick M. J. Interferon action: inhibition of vesicular stomatitis virus RNA synthesis induced by virion-bound polymerase. Science. 1971 Nov 5;174(4009):593–598. doi: 10.1126/science.174.4009.593. [DOI] [PubMed] [Google Scholar]
  19. Niblack J. F., McCreary M. B. Relationship of biological activities of poly I-poly C to homopolymer molecular weights. Nat New Biol. 1971 Sep 8;233(36):52–53. doi: 10.1038/newbio233052a0. [DOI] [PubMed] [Google Scholar]
  20. PAUCKER K., CANTELL K., HENLE W. Quantitative studies on viral interference in suspended L cells. III. Effect of interfering viruses and interferon on the growth rate of cells. Virology. 1962 Jun;17:324–334. doi: 10.1016/0042-6822(62)90123-x. [DOI] [PubMed] [Google Scholar]
  21. Pitha P. M., Carter W. A. The DEAE dextran:polyriboinosinate-polyribocytidylate complex: physical properties and interferon induction. Virology. 1971 Sep;45(3):777–781. doi: 10.1016/0042-6822(71)90194-2. [DOI] [PubMed] [Google Scholar]
  22. Rosztóczy I., Mécs I. Enhancement of interferon synthesis by polyinosinic-polycytidylic acid in L cells pretreated with interferon. Acta Virol. 1970 Sep;14(5):398–400. [PubMed] [Google Scholar]
  23. Stewart W. E., 2nd, Gosser L. B., Lockart R. Z., Jr Distinguishing characteristics of the interferon responses of primary and continuous mouse cell cultures. J Gen Virol. 1971 Oct;13(1):35–50. doi: 10.1099/0022-1317-13-1-35. [DOI] [PubMed] [Google Scholar]
  24. Stewart W. E., 2nd, Gosser L. B., Lockart R. Z., Jr Priming: a nonantiviral function of interferon. J Virol. 1971 Jun;7(6):792–801. doi: 10.1128/jvi.7.6.792-801.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Youngner J. S., Hallum J. V. Inhibition of induction of interferon synthesis in L-cells pretreated with interferon. Virology. 1969 Mar;37(3):473–475. doi: 10.1016/0042-6822(69)90231-1. [DOI] [PubMed] [Google Scholar]

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