Control of Interferon Synthesis: Effect of Diethyl-aminoethyl-Dextran on Induction by Polyinosinic-Polycytidylic Acid

Abstract

Interferon production in cultures of rabbit kidney cells (RKC) stimulated with 10 to 250 μg of polyinosinic-polycytidylic acid (poly I·poly C) per ml peaked at 3 to 4 hr after the exposure of cells to inducer and rapidly declined thereafter. On the other hand, RKC stimulated with poly I·poly C (10 or 2 μg/ml) in the presence of diethylaminoethyl (DEAE)-dextran (100 or 20 μg/ml, respectively) produced a protracted interferon response, with the release of interferon continuing for over 24 hr. The kinetics of interferon production in RKC stimulated with lower concentrations of the mixture of poly I·poly C and DEAE-dextran were similar to the response produced by poly I·poly C alone (10 to 250 μg/ml). Only the responses that terminated early were paradoxically enhanced by treatment with low doses of actinomycin D or with cycloheximide. Cells stimulated with 50 μg of poly I·poly C/ml showed hyporesponsiveness to a second interferon induction with poly I·poly C when restimulated 7 hr after primary induction. This hyporesponsiveness could be overcome by restimulating with higher concentrations of the poly I·poly C-DEAE-dextran complex. The results are compatible with the hypothesis that the early termination of interferon production and hyporesponsiveness to repeated induction with poly I·poly C are due to a cellular repressor exerting negative control on interferon synthesis, and that the increased cellular uptake of poly I·poly C in the presence of DEAE-dextran may effectively neutralize the repressor. These results also suggested that the often observed different kinetics and the varied effects of inhibitors of ribonucleic acid or protein synthesis on interferon responses in various cells and in cells stimulated with different inducers (such as with viruses as compared with polynucleotides) need not imply the existence of fundamentally different mechanisms of interferon production.