Regulation of Macrophage Growth and Antiviral Activity by Interferon-γ

• Published in: The Journal of cell biology Vol. 109; no. 3; pp. 1331 - 1340
• Main Authors: Goldberg, Michael, Belkowski, Linda S., Bloom, Barry R.
• Format: Journal Article
• Language: English
• Published: New York, NY Rockefeller University Press 01.09.1989; The Rockefeller University Press
• Subjects: 2',5'-Oligoadenylate Synthetase - metabolism; Analysis of the immune response. Humoral and cellular immunity; Animals; Antivirals; Biological and medical sciences; Cell Division - drug effects; Cell growth; Cell Line; Cell lines; Cells; Clone Cells; Encephalomyocarditis virus - growth & development; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression regulation; Genes; Immunobiology; Interferon Type I - pharmacology; Interferon-gamma - pharmacology; Interferons; Kinetics; L cells; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - physiology; Miscellaneous; Recombinant Proteins; Regulatory factors and their cellular receptors; RNA, Neoplasm - isolation & purification; Somatic cells; Vesicular stomatitis Indiana virus - growth & development; Cell proliferation; Cell culture; Virus multiplication; RNA; Cytokine; Biological activity; Assay; Northern blotting; Enzymatic activity; Protein kinase; (2',5')A-Synthetase; Antiviral; Nucleic acid; Gamma interferon; Macrophage
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.109.3.1331

Interferons, in addition to their antiviral activity, induce a multiplicity of effects on different cell types. Interferon (IFN)-γ exerts a unique regulatory effect on cells of the mononuclear phagocyte lineage. To investigate whether the antiviral and antiproliferative effects of IFN-γ in macrophages can be genetically dissociated, and whether IFN-α and IFN-γ 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-γ. Two different classes of variants were found: those resistant to the antiproliferative and antiviral effects of IFN-γ against vesicular stomatitis virus (VSV) and those resistant to the antiproliferative effect, but protected against VSV and encephalomyocarditis virus (EMCV) lysis by IFN-γ. 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-γ. Analysis of these mutants has provided several insights regarding the regulatory mechanisms of IFN-γ and IFN-α on the murine macrophage cell lines. The antiproliferative activity of IFN-γ on these cells, in contrast to that of IFN-α, is mediated by a cAMP-independent pathway. The antiproliferative and antiviral activities of IFN-γ 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-α and IFN-γ regulate the induction of the dsRNA-dependent Pl/eIF-2α protein kinase and 2′,5′-oligoadenylate synthetase enzymatic activities via different pathways. Finally, a unique macrophage mutant was obtained that was protected by IFN-γ 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.