Cellular Mechanisms of Interferon Production

Abstract

Rabbit kidney cell cultures stimulated with either double-stranded polyinosinate-polycytidylate (poly I:poly C) or with ultraviolet-irradiated Newcastle disease virus (UV-NDV) produce two types of interferon response, designated "early" and "late," respectively. The early response is suppressed by inhibitors of RNA or protein synthesis and is therefore thought to represent de novo synthesis of interferon. Circumstantial evidence suggested that this interferon response is regulated by a translation control mechanism. Late interferon production with poly I: poly C only took place in the presence of inhibitors of RNA or protein synthesis. The late interferon is therefore likely to be derived by the activation of an interferon precursor. The stimulation of late poly I: poly C-induced interferon production by cycloheximide suggested the existence of a second, posttranslational level of control of interferon production. This posttranslation control seems to be activated by interferon. UV-NDV can probably suppress the synthesis of the posttranslation inhibitory protein, and therefore it stimulates a late interferon response in the absence of inhibitors of RNA or protein synthesis. It is postulated that both the translation and posttranslation inhibitor participate in the development of a cellular refractory state to repeated interferon stimulation. The picture of interferon which emerges from this study is one of a heterogenous class of proteins whose production is controlled by cellular repressors acting at various levels.

In Vivo Release of Previously Cleared Interferon by Cycloheximide

“…Perhaps a greater number of cells or other unique cells are required to demonstrate this effect. Alternatively, and most favored by us, is the present interpretation of others (11)(12)(13) that "in vitro" cycloheximide superinduction is due to another mechanism, which is inhibition of production of a regulatory substance.…”

“…The data reported herein confirm the interferon "superinduction" phenomenon previously reported with metabolic inhibitors in vivo (1,15) and offer a possible explanation for this phenomenon in vivo, on the basis of a release of previously cleared interferon. That the superinduction phenomenon in vivo cannot be entirely explained TABLE by inhibition of synthesis of a repressor substance (12,13) is substantiated by the fact that cycloheximide causes a second peak of serum interferon even though the interferon being cleared was administered exogenously and in some experiments was heterologus and hence did not require interferon synthesis by the host. Thus, the synthesis of a repressor substance would be unnecessary in this situation.…”

“…Early in vivo work (14-17) with various inducers led to the conclusion that the production of interferon by some inducers, such as viruses, required de novo protein synthesis, whereas other interferon inducers, such as endotoxins, caused release of preformed interferon. Later work, both in vivo and in cell cultures (11)(12)(13)(14), cast doubt on this hypothesis, particularly the observation of the phenomenon of "superinduction" in which inhibitors of protein synthesis actually enhanced interferon production. To explain this enhancement, it was speculated that metabolic inhibitors might prevent synthesis of a repressor substance which normally shuts off interferon production (12,13).…”

Refractory State of Cells to Interferon Induction

“…Contradictory results were punished in the case of poly I: C induced interferon. The priming effect is present in most of the cases, however a blocking effect is not always reported (Tan et al I97o;Vilcek, 197o;Stewart et al I971a;Margolis et al 1972). In our system, as for Youngner & Hallum (1969) and Stewart et al (1971a), a blocking effect is clearly shown; it is possible that the blockage of interferon synthesis is not due to the same mechanism in the case of a virus induction and in the case of induction by poly I : C (Bausek & Merigan,I97O).…”

Induction of Viral Interference: Effects of Poly rI·rC and Diethylaminoethyl-Dextran on the Activity of the Antiviral Protein

“…Usually, the tissue culture fluids from cells stimulated to produce interferon are assayed in another set of cell cultures which is at least one step removed from the events occurring in the originally stimulated cells. It is generally accepted that interferon itself is not antiviral, but it stimulates yet another host function which is commonly referred to as the antiviral protein (9,20,23). This is the protein which prevents viral replication by inhibiting the translation of viral messenger ribonucleic acid (mRNA) (11,15).…”