Inducers of Interferon Inhibit the Mitotic Response of Liver Cells to Partial Hepatectomy

Abstract

Partially hepatectomized mice were injected with inducers of interferon, and the mitotic activity of liver cells was measured. The inducers were polyriboinosinic * polyribocytidylic acid, poly(I * C), Newcastle disease virus, and statolon. Each inhibited the mitosis of liver cells. Poly(I-C) was effective in doses as low as 1 ug per mouse. Polyriboinosinic acid, poly(I), had no inhibitory effect. These results extend the spectrum of action of inducers of interferon to inhibition of mitotic division of an aneoplastic, nonaneuploid mammalian cell.The possibility that interferon and its inducers might inhibit the multiplication of mammalian cells has often been considered. Protection against transplantable tumors has been achieved with interferon (1) and its inducers (2), and chemically induced tumorigenesis has been inhibited by poly(I -C) (3). However, mechanisms other than direct inhibition of multiplication of tumor cells, such as enhancement of immune responses or other indirect effects exerted through the host, could have been involved. Studies of the effects of interferon on cell cultures have been complicated by the unavailability of pure preparations of interferon, since the impurities might have growth-inhibitory effects. Initial reports of such studies were conflicting (4), but recent experiments with preparations derived from various sources suggest that interferon may inhibit multiplication of an established mouse tumor cell line (5). Isoproterenol-induced DNA synthesis in salivary-gland epithelium was inhibited by poly(I* C) (6), but it was not stated whether other inducers of interferon were capable of the same effect. It was also not known whether poly(I .C) was effective only against isoproterenol-induced DNA synthesis, or whether it had a more general inhibitory effect on the division of normal cells.We have now studied the effect of several inducers of interferon on the mitotic division of liver cells that is stimulated by partial hepatectomy; we find that division of such cells is inhibited. MATERIALS AND METHODS Hepatectomy7-week-old, female, CF1 mice (Carworth farms), weighing 19-23 g, were anesthetized with-sodium pentobarbital (0.6 mg/mouse) given intraperitoneally, supplemented by inhalation of ether. Ligatures were tied around the left lateral and median lobes of the liver and most of the median lobe and two-thirds of the left lateral lobe were removed and weighed. The total liver weight (determined in other mice of the same age and weight) ranged from 1.1 to 1.7 g. The portion of liver removed usually weighed from 0.6 to 0.85 g. Mice were matched after hepatectomy so that median weights and ranges of weight of excised liver were nearly equal in all groups of the same experiment. Measurement of mitotic activityMice were killed by cervical dislocation. Specimens from the right lateral lobe of the liver were fixed in Carnoy's solution and sections were stained with hematoxylin and eosin. The mitotic nuclei and interphase nuclei of the parenchymal cells were enumerated with the help o...

Poly(Inosinic Acid)·Poly(Cytidylic Acid) Inhibition of DNA Synthesis in Synchronized HeLa Cells

“…Poly(I C) may generally enhance the immunological ability of the host and exclude antigenically different tumor cells. Recent evidence shows that poly(I * C) inhibits isoproterenol-stimulated DNA synthesis in the mouse salivary gland (12), phytohemagglutinin-stimulated DNA synthesis in lymphocyte incubations (14), and rat liver cell mitosis induced by partial hepatectomy (13). Furthermore, our study shows that the double-stranded synthetic RNA inhibited synchronized HeLa cell DNA synthesis.…”

“…Poly(I C) blocks carcinogenesis by dimethylbenzanthracene (11). In addition it inhibits isoproterenol-stimulated DNA synthesis in salivary glands of mice (12), rat liver cell divisions stimulated by partial hepatectomy (13). Poly(A * U) depresses phytohemagglutinin-induced DNA synthesis in lymphocyte culture (14).…”

Mitogenesis in normal human fibroblasts by polyinosinic · polycytidylic acid and other synthetic acidic polymers: Enhancement of action by glucocorticoids

“…In this respect, it is important to note that the mitogenic action of poly I *poly C in fibroblasts (our study) is in marked contrast to the observations that poly I *poly C is both a potent inhibitor of tumor growth (Mohr et al, 1972) and an inhibitor of DNA synthesis in synchronized HeLacells (Teng et al, 1973), isoproterenol-stimulated salivary glands (Serota and Raserga, 1970). and regenerating liver cells (Jahiel et al, 1971).…”

Antiviral activities of interferons

“…Inoculation of hamsters with poly(rI).poly(rC) resulted in the discovery of a hemopoetic cell-colony formation inhibitor in the serum of these animals by McNeill and his colleagues (McNeill and Fleming, 1971;Fleming et al, 1972;McNeill et al, 1972). Interferon inducers [poly(rI).poly(rC), Newcastle disease virus and statolon] were reported to inhibit the mitotic response of liver cells to partial hepatectomy (Jahiel et al, 1971); later interferon itself was shown to have the same effect (Frayssinet et al, 1973).…”