Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents.

Abstract

Treatment of human fibroblast FS4 cultures with human type II interferon preparations induced the synthesis of at least four proteins that were similar in size to four of the five proteins induced by type I interferons (Mr 120,000, 88,000, 67,000, and 56,000). However, the M, 67,000 and 56,000 proteins were induced more strongly by type II than by type I interferon, and a counterpart of a Mr 80,000 protein induced by type I interferons was not noticeably induced by type II interferon preparations. We therefore compared type I and type II interferons for relative antiviral activities against different viruses (vesicular stomatitis, encephalomyocarditis, and vaccinia viruses and reovirus) and for cell growth-inhibitory activities on various cell types. The replication of vesicular stomatitis and encephalomyocarditis viruses was inhibited more strongly by type I interferon, whereas reovirus and vaccinia virus showed greater sensitivity to type II interferon preparations. This indicates that viruses may differ in their sensitivity to human type I and type II interferons and that the antiviral mechanisms induced by type I and type II interferons may have significant differences. The type I and type II interferons may also differ in their efficacies as antiproliferative agents. Type II interferon preparations at 2.5 units/ml inhibited the incorporation of [3H]thymidine to a greater extent than did type I interferon at 400 units/ml. (For both type I and type II interferons, the unit of interferon activity was defined as the concentration that decreased the yield of vesicular stomatitis virus by 50% in FS-4 cultures.) Furthermore, whereas type II interferon preparations had a reversible cytostatic effect on normal human fibroblasts at 10 units/ml, the transformed cells tested (HeLa, osteosarcoma, U-amnion) showed extensive cell death, thus indicating that it may have a cytocidal effect on certain tumor cells. It appears that human type II interferon (or a factor present in these preparations) may be a potent antitumor agent.Interferons are classified into two groups, called type I and type II interferons, which differ in their acid stability, their antigenic properties, and the nature of stimulus required for their production (reviewed in refs. 1 and 2). The human fibroblast and leukocyte interferons, so named because of their cellular origins, are both acid stable and are thus classified as type I interferons, although they are antigenically different. On the other hand, the interferon produced by human leukocytes in response to mitogenic or specific antigenic stimuli is acid labile and is classified as type II (or immune) interferon. This type II interferon activity is not neutralized by antisera raised against human fibroblast or leukocyte interferons and therefore appears to be distinct (3, 4).The antiviral action of type I interferons requires the expression of certain cellular genes because it is blocked by inhibitors of either transcription or translation (5-8) or by enucleation of cells (9, 10). Our stu...

Interferon-induced human protein with homology to protein Mx of influenza virus-resistant mice.

“…2 and 3), cultured skin fibroblasts from newborn or adult donors, and some transformed or tumor cell lines (data not shown). Human fibroblast proteins with apparent molecular sizes of about 80,000 Da that are strongly induced by IFN-a but not detectably induced by IFN-y have previously been described by two other groups (7,11). It remains to be determined whether one of these proteins and the 2C12-cross-reacting protein are identical.…”

“…They induce in responsive cells the synthesis of several proteins that are not detected or do exist at much lower concentrations in untreated cells. Induced proteins in mouse and human cells have been widely studied (1,5,7,10,11; for a review, see reference 6), but most of them are still poorly characterized. Also, little is known about the functional, structural, and evolutionary relationships of distinct proteins induced in cells of different species.…”

A cytotoxic substance (CTS-51) produced by human buffy coat cultures stimulated by Staphylococcal enterotoxin B: Further characterizations and combined action with interferon.

“…CTS-51 was isolated in the process of the immune interferon production. However it does not show any antiviral activity at all, and the cytotoxic activity of CTS-51 is preserved even after the acid treatment at pH 2.0 for 24 hr, where IFN-y is known to be inactivated (Rubin and Gupta 1980). These observations seem to deny the possibilities that CTS-51 is one of the immune interferons nor that the cytotoxic activity of IFN-y preparations may be exerted by this cytotoxic substance contaminated in them.…”

“…Some of these factors, such as, for example, interferons and interleukin-2, are revealed to have a property to potentiate the cytotoxic activities of several cellular immunological systems, such as, for example, natural killer cell system or MLC derived cell mediated cytotoxicity system (Heron et al 1976(Heron et al , 1979Marx 1983). On the other hand, several other cytokines have been reported to have a property directly cytotoxic to the target cells in vitro, which include lymphotoxins (Evans 1982), tumor necrosis factors (williamson et al 1983), natural killer cytotoxic factors (Bonavida et al 1982) and immune interferons (Rubin and Gupta 1980).…”

Recombinant Human Interferon- Inhibits Adenovirus Multiplication without Modifying Viral Penetration

“…The lack of anti-adenovirus action of rlFN-~ suggests that the effect of rlFN-y depends on some mechanism(s) not shared by rlFN-a. The possibility of rlFN-y acting by a different antiviral mechanism was previously discussed by Rubin & Gupta (1980), who showed that vaccinia virus and reovirus were sensitive to IFN-y but not to IFN-a. Weil et al (1983) have shown the synthesis after rIFN-7 treatment of at least eight polypeptides not induced by rIFN-e. Antiviral states induced by IFN-cc/fl and IFN-y have been shown to be regulated with different kinetics, for both induction and extinction (Ramamurthy & Fleischmann, 1986).…”