Goldberg M, Belkowski L S, Bloom B R
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
J Cell Biol. 1989 Sep;109(3):1331-40. 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)-gamma exerts a unique regulatory effect on cells of the mononuclear phagocyte lineage. To investigate whether the antiviral and antiproliferative effects of IFN-gamma in macrophages can be genetically dissociated, and whether IFN-alpha and IFN-gamma 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-gamma. Two different classes of variants were found: those resistant to the antiproliferative and antiviral effects of IFN-gamma against vesicular stomatitis virus (VSV) and those resistant to the antiproliferative effect, but protected against VSV and encephalomyocarditis virus (EMCV) lysis by IFN-gamma. 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-gamma. Analysis of these mutants has provided several insights regarding the regulatory mechanisms of IFN-gamma and IFN-alpha on the murine macrophage cell lines. The antiproliferative activity of IFN-gamma on these cells, in contrast to that of IFN-alpha, is mediated by a cAMP-independent pathway. The antiproliferative and antiviral activities of IFN-gamma 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-alpha and IFN-gamma regulate the induction of the dsRNA-dependent P1/eIF-2 alpha protein kinase and 2',5'-oligoadenylate synthetase enzymatic activities via different pathways. Finally, a unique macrophage mutant was obtained that was protected by IFN-gamma 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.
干扰素除了具有抗病毒活性外，还对不同细胞类型产生多种作用。γ干扰素（IFN-γ）对单核吞噬细胞系细胞发挥独特的调节作用。为了研究巨噬细胞中IFN-γ的抗病毒和抗增殖作用是否可以在遗传上分离，以及IFN-α和IFN-γ是否使用相同的细胞信号和/或效应机制来实现其生物学效应，我们获得了一系列对IFN-γ的抗增殖和/或抗病毒活性具有抗性的体细胞遗传变体。发现了两类不同的变体：一类对IFN-γ针对水泡性口炎病毒（VSV）的抗增殖和抗病毒作用具有抗性，另一类对IFN-γ的抗增殖作用具有抗性，但能免受VSV和脑心肌炎病毒（EMCV）裂解。此外，还获得了第三类突变体，其对IFN-γ的生长抑制活性敏感，但对其抗病毒活性具有抗性。对这些突变体的分析为IFN-γ和IFN-α对小鼠巨噬细胞系的调节机制提供了一些见解。与IFN-α不同，IFN-γ对这些细胞的抗增殖活性是由一条不依赖cAMP的途径介导的。IFN-γ的抗增殖和抗病毒活性在遗传上是分离的。获得了对生长具有抗性但受到抗病毒保护的变体，或者是生长受到抑制但对VSV或EMCV没有抗病毒保护的变体。遗传分析表明IFN-α和IFN-γ通过不同途径调节双链RNA依赖性P1/eIF-2α蛋白激酶和2',5'-寡腺苷酸合成酶的酶活性。最后，获得了一个独特的巨噬细胞突变体，它受到IFN-γ的保护而免受VSV感染，但不能免受EMCV感染，这表明针对这些不同类型RNA病毒的抗病毒机制在某种程度上必然是不同的。
