The interferons are a widely studied group of proteins which were first identified by their ability to protect cells against virus infections (Stewart, 1979). They are synthesized and secreted by a variety of cell types in response to several classes of inducers (notably virus infections) and exert their effects in vivo as a result of interaction with other cells in distant parts of the body. In this sense the interferons are analogous to the polypeptide hormones. A functional similarity with hormones is further emphasized by the recent identification in target cells of specific membrane receptors for interferons and by the multiplicity of biological effects which result from the interactions of the interferons with these receptors. In recent years it has become clear that the interferons are capable of influencing cellular physiology and behaviour in a number of ways. Their effects include inhibition of cell growth and proliferation, regulation of the expression of specific genes, modulation of cell differentiation, and activation of certain cell types in the immune system (e.g. macrophages and natural killer cells). The mechanisms underlying the antiviral actions of the interferons have been widely studied and frequently reviewed (Baglioni, 1979; Hovanessian, 1979; Lengyel, 1982; Sen, 1982). In contrast, information concerning the effects of interferons on cell proliferation and differentiation has only been obtained during the last decade, as our understanding ofmechanisms ofgrowth regulation and gene expression in eukaryotes in general has increased. This review aims to summarize the current situation regarding these actions of the interferons and suggests areas in which our perception of such control of cell function may be expected to increase.

Regulation of cell proliferation and differentiation by interferons.

c-myc gene mRNA is reduced by greater than 75% in the human lymphoblastoid cell line Daudi when growth is inhibited by treatment with human interferon beta (IFN-beta). In the present communication, we describe the effect of IFN-beta treatment on transcription of the c-myc gene and on the steady-state level of c-myc mRNA in the cytoplasm of Daudi cells. The results show that, although the rate of c-myc transcription is not significantly different in nuclei isolated either from untreated cells or from those treated with IFN-beta for 3 or 24 hr, the level of c-myc mRNA in the cytoplasm is reduced by 60% within 3 hr of IFN-beta treatment. These results suggest that IFN-beta regulates the c-myc mRNA at a post-transcriptional level. These results are in contrast to the regulation of two IFN-beta-induced genes that under identical conditions are regulated in these cells at the transcriptional level. We have also detected induction of the (2'-5')oligoadenylate synthetase (2-5A synthetase) gene in IFN-beta-treated Daudi cells. Since certain c-myc transcripts have the capacity to form double-stranded RNA regions, we propose that one mechanism by which c-myc could be regulated post-transcriptionally in IFN-beta-treated cells is by activating, through its own double-strandedness, the 2-5A synthetase/RNase L endonuclease system, which would cause selective degradation of the c-myc RNA.

Interferon regulates c-myc gene expression in Daudi cells at the post-transcriptional level.

Under normal growth conditions, the human lymphoblastoid cell line Daudi expresses high levels of c-myc mRNA. These cells are also sensitive to growth inhibition by interferons. We have compared the levels of mRNA for the c-myc in untreated and human beta interferon (IFN-beta)-treated Daudi cells by RNA dot-blot and blot-hybridization analysis methods. Using a synthetic oligonucleotide complementary to the human c-myc mRNA as the probe, we detected a more than 75% reduction in the c-myc hybridizable poly(A)+ RNA in the IFN-beta-treated cells. This reduction in the c-myc mRNA appears to be selective because the level of actin mRNA is not significantly affected by the IFN-beta treatment. In addition, neither in vitro translation of mRNA extracted from IFN-beta-treated cells nor in vivo synthesis of cellular proteins in IFN-beta-treated cells are quantitatively affected. We surmise that the selective reduction in the amount of c-myc mRNA in IFN-beta-treated Daudi cells may be related to the IFN-induced inhibition of the Daudi tumor cell growth.

https://www.pnas.org/content/pnas/81/6/1747.full.pdf

Selective reduction of c-myc mRNA in Daudi cells by human beta interferon

Human leukocyte interferon subtypes have different antiproliferative and antiviral activities on human cells

The Daudi line of human lymphoblastoid cells shows a high sensitivity towards growth inhibition by human interferons. In cells pretreated with 70 reference units/ml of an interferon preparation for 48 h, the incorporation of exogenous [3H]thymidine into DNA is inhibited by as much as 85%. We are investigating the extent to which this effect reflects a true inhibition of the rate of DNA synthesis or whether it may be caused by changes in the metabolic utilization of exogenous thymidine by the cells. Interferon treatment results in a 30% inhibition of the rate of membrane transport and a 60% decrease in the rate of phosphorylation of [3H]thymidine in vivo. The latter effect is due to a decrease in V of thymidine kinase without any change in the value of Km for this enzyme. In addition to these changes, incorporation of [3H]uridine into DNA, which occurs as a result of the intracellular conversion of this precursor into thymidine nucleotides, is also inhibited by 75%, whereas RNA labelling by [3H]uridine is decreased by only 15% in interferon-treated cells. Thus several different metabolic events associated with thymidine nucleotide metabolism and DNA synthesis in Daudi cells are disrupted by interferon treatment.

Inhibition of cell division by interferons: Changes in the transport and intracellular metabolism of thymidine in human lymphoblastoid (Daudi) cells.

Human interferon (HIF) preparations inhibited the propagation of Daudi cells in stationary suspension cultures, while a control preparation showed no such effect. The growth inhibition (= anticellular) activity of differently pretreated HIF preparations was determined by the reduction of14C-labelled thymidine (14C-TDR) uptake in a microassay system. These studies demonstrated that the degree of anticellular activity is directly proportional to the antiviral activity of different HIF preparations. These preparations were obtained from peripheral leukocytes (lHIF) or diploid fibroblasts (fHIF). Together with gel chromatography results, and the sensitivity of the anticellular activity to tryptic digestion and heat inactivation, these results suggest that the anticellularly active substance is a protein which is very similar to, or identical with, interferon.

Growth inhibition of human lymphoblastoid Daudi cells in vitro by interferon preparations.

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Growth inhibition of human lymphoblastoid Daudi cells in vitro by interferon preparations.