Post-transcriptional control of interferon synthesis.

Low to moderate doses of cycloheximide had a stimulatory effect on interferon production in rabbit kidney cell cultures treated with double-stranded polyinosinate-polycytidylate (poly I:poly C). A very marked stimulation occurred in the presence of a dose of cycloheximide inhibiting amino acid incorporation into total cellular protein by about 75%. Higher doses of cycloheximide caused a shift in interferon release towards later intervals and a gradual decrease in the overall degree of stimulation. An even greater increase in the amount of interferon produced was observed if cells were treated with cycloheximide for only 3 to 4 hr immediately after their exposure to poly I:poly C. Under the latter conditions, a rapid burst of interferon production occurred after the reversal of cycloheximide action. Treatment with a high dose of actinomycin D before the reversal of cycloheximide action caused a further increase and a marked prolongation of interferon production. It is postulated that inhibitors of protein synthesis suppress the accumulation of a cellular regulatory protein (repressor) which interacts with the interferon messenger ribonucleic acid mRNA and thereby prevents its translation. Therefore, active interferon mRNA can apparently accumulate in rabbit kidney cells which, after exposure to poly I:poly C, are kept in the presence of an inhibitor of protein synthesis. Some of this accumulated interferon mRNA can be translated during a partial block of cellular protein synthesis, but its most efficient translation occurs after the reversal of the action of the protein synthesis inhibitor.