The addition of appropriate doses of interferon (IF) to cultures of Friend erythroleukemic cells inhibits dimethyl sulfoxide (Me2SO)-stimulated erythroid differentiation. In this study, the synthesis of heme, hemoglobin, and globin mRNA in Me2SO-stimulated cultures, with or without IF added, was compared. Although the hemoglobin content in Me2SO+IF-treated cultures was reduced 6- to 9-fold compared to that of cultures treated with Me2SO alone, there was less than a 2-fold decrease in the amount of heme accumulated. Globin mRNA, although unchanged in size or base sequence, was reduced in content in the Me2SO+IF cultures. The level of reduction of globin mRNA was insufficient to account for the lack of globin synthesis. Thus, it appears that IF may operate on two levels--one involving the transcription of globin mRNA and the other involving its translation.
The administration of appropriate doses of interferon to cultures of Friend leukemia cells causes a pronounced inhibition of cell growth. Several lines of evidence indicate that this effect is due to interferon itself, rather than to unknown contaminants of interferon preparations.Autoradiograph analysis of growth parameters of Friend leukemia cells during treatment with interferon demonstrates that the rate of entry into the S phase, the percent decline of unlabeled mitoses, and the mitotic indexes are significantly lower in interferon-treated cell cultures than in control untreated cultures when tritiated thymidine was added 12 h after the administration of interferon. These data indicate that fractions of interferon-treated cell population are delayed in both G1 and in G2 phases of the cell cycle. This was confirmed by exact measurements of the length of the various phases of the cycle.The interferon-induced inhibition of growth of Friend leukemia cells is reversible after removal of the compound. Autoradiograph data obtained from control cultures and from cultures previously treated with interferon that had been washed free of interferon and reseeded in interferon-free medium, demonstrate that during the first 12 h after removal of interferon, a large majority of the cells previously treated with interferon had a deranged flow into the S phase, a high number of unlabeled mitoses, and a low mitotic index. These data provide further evidence for the above-mentioned prolongations of G1 and G2 phases of the cell cycle. All growth parameters tested reverted to normal values within 12 h after washing out interferon.
KEY WORDS interferoncell growth cell cycle Friend cellsInterferon preparations exhibit an inhibitory effect on the multiplication of both normal (12, 15) and neoplastic cells (8,11,17), without any significant effect on cell viability. Extensive studies on the effect of interferon on the division cycle of growthinhibited L1210 cells in vitro pointed out that this phenomenon was seemingly due to a decrease in the doubling potential of each interferon-treated cell (17). We had previously shown that interferon also inhibits the multiplication of Friend virus (FLV)-induced erythroleukemic cells (4) in the spleens of irradiated and nonirradiated, histocompatible DBA/2 mice (22).The data presented here show that the inhibitory effect of interferon on the growth of Friend leukemia cells in vitro is reversible. Autoradi-344
The RNA synthesis of human leukemic leukocytes and phytohemagglutinin-stimulated lymphocytes is markedly reduced by administration of a low-molecular-weight nonhistone peptide factor from calf thymus. Treatment with the factor strongly inhibits hemoglobin production and globin mRNA transcription in dimethyl sulfoxide-stimulated Friend cells without appreciably modifying the rate of cell growth. Evidence for specificity of these effects is provided by the lack of action of the factor on both growth rate and RNA synthesis of a number of nondifferentiating cell lines from various animal species. After removal of the compound, both human lymphocytes and Friend cells can be stimjK'a&ed by phytohemagglutinin and by dimethyl sulfoxide, respectively, ruling out any toxic effect.We have previously isolated, from aqueous extracts of calf thymus, an active factor, which has been partially purified by DEAE-cellulose and Dowex 50WX2 chromatography and characterized as a peptide of less than 5000 molecular weight (1). This factor causes a strong inhibition of DNA-directed (1) or chromatin-directed (2) RNA polymerase reactions in vitro.
SUMMARYThe effect of mouse interferon (ITF) on the expression of Friend leukaemia virus (FLV) and on dimethyl sulphoxide (DMSO)-stimulated haemoglobin synthesis in Friend erythroleukaemic cells (FLC) was studied. Immunofluorescent staining was used to detect intracellular antigens, and incorporation of ~H-uridine into virions to detect extracellular virus release. Interferon markedly inhibited haemoglobin synthesis and FLV production, but enhanced accumulation of virus antigens in the cytoplasm; on the cell surface, however, FLV antigens were present to the same extent whether ITF was present or not. When ITF was removed, virus production rose and intracellular virus antigens fell to the levels of untreated controls.
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