Regulation of macrophage growth and antiviral activity by interferon-gamma.

Abstract

Abstract. Interferons, in addition to their antiviral activity, induce a multiplicity of effects on different cell types. Interferon (IFN)-3, exerts a unique regulatory effect on cells of the mononuclear phagocyte lineage. To investigate whether the antiviral and antiproliferative effects of IFN-~ in macrophages can be geneticaUy dissociated, and whether IFN-ot and IFN-3, use the same cellular signals and/or effector mechanisms to achieve their biologic effects, we have derived a series of somatic cell genetic variants resistant to the antiproliferative and/or antiviral activities of IFN-3,. Two different classes of variants were found: those resistant to the antiproliferative and antiviral effects of IFN-'t against vesicular stomatitis virus (VSV) and those resistant to the antiproliferative effect, but protected against VSV and encephalomyocarditis virus (EMCV) lysis by IFN-~. In addition, a third class of mutants was obtained that was susceptible to the growth inhibitory activity, but resistant to the antiviral activity of IFN-7. Analysis of these mutants has provided several insights regarding the regulatory mechanisms of IFN-3, and IFN-o~ on the murin¢ macrophage cell lines. The antiproliferative activity of IFN-3, on these cells, in contrast to that of IFN-ot, is mediated by a cAMP-independent pathway. The antiproliferative and antiviral activities of IFN-3, were genetically dissociated. Variants were obtained that are growth resistant but antivirally protected, or are growth inhibited but not antivirally protected against VSV or EMCV. The genetic analysis indicated that IFN-~ and IFN--y regulate the induction of the dsRNA-dependent P1/eIF2a protein kinase and 2',5'-oligoadenylate synthetase enzymatic activities via different pathways. Finally, a unique macrophage mutant was obtained that was protected by IFN-'y against infection by VSV, but not EMCV, suggesting that antiviral mechanisms involved in protection against these different types of RNA viruses must be distinct at some level.

Induction by vasoactive intestinal peptide of interferon α/β synthesis in glial cells but not in neurons

“…We showed here that such functional binding sites are present in both glial and neuronal cultures. Goldberg et al (1989) have shown that the antiproliferative effect of IFN (Y in the 5774.2 macrophage cell line is mediated by a CAMP-dependent pathway. Moreover, it is also known that adrenaline, theophylline, and l-methyl-3-isobutylxanthine, which elevated cAMP concentrations, also induce 2'5'A synthetase and antiviral activities (Itkes et al, 1982(Itkes et al, ,1984.…”

Differential Effects of Bacterial Lipopolysaccharide and Interferon-.GAMMA. on Proliferation of Two Factor-Dependent Macrophage Cell Lines.

“…3). Because LPS-treated BDM-1W3 cells incorporated BrdU into their nuclei and the incorporation of BrdU was completely inhibited by a DNApolymerase a inhibitor, aphidicolin (Table I) ) and a macrophage cell line (10). In our study IFN-f inhibited the proliferation of BDM-1and BDM-1W3 cells dose dependency (Fig.…”

“…IFN-f has been shown to inhibit the proliferation of peritoneal (30) and bone marrow-derived macrophages (5, 27) and macrophage cell line (10). In order to further characterize the differential effects of LPS and IFN-f on the functions of our macrophage cell lines, we investigated the effects of LPS, IFN-7, and TNF-a on the proliferation of two factor-dependent macrophage cell lines, BDM-1, and its subclone, BDM-1W3.…”

Increase of Epidermal Growth Factor Receptor Expression Associated with a Lack of Antiproliferative Effect of IFN-β in Human Lung Cancer Nodules in Organotypic Culture

“…The recent selection of mutants resis tant to IFN-a but unexpectedly responding to IFN-P [26] is in agreement with this hy pothesis. Such findings suggest that IFN-a and IFN-P interact differently with a single type of receptor, unless there exists an addi tional receptor specific for IFN-p. At any rate, the signal transduction mechanisms in mediating the antiproliferative effects of IFNs are still largely unknown, even though differential signalling pathways involving cy clic AMP [27] and inositolphosphates [28] are evoked.…”