Multifaceted activities of type I interferon are revealed by a receptor antagonist.
Multifaceted activities of type I interferon are revealed by a receptor antagonist.
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I型干扰素的多方面活性由受体拮抗剂揭示。
DOI：
10.1126/scisignal.2004998
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发表时间：
2014-05-27
影响因子：
7.3
通讯作者：
Schreiber G
中科院分区：
文献类型：
--
作者：
Levin D;Schneider WM;Hoffmann HH;Yarden G;Busetto AG;Manor O;Sharma N;Rice CM;Schreiber G
I型干扰素是一类同源的多功能细胞因子家族，包括多种干扰素-α亚型和干扰素-β。IFN通过与共同的受体结合来激活不同的细胞反应，该受体由两个亚单位组成，即IFNAR1和IFNAR2。除了刺激抗病毒反应外，它们还抑制细胞增殖和调节其他免疫反应。我们鉴定了各种干扰素，包括一种突变型干扰素-α2(干扰素-1ant)，它与干扰素受体2紧密结合，但显著减少了与干扰素受体1的结合。虽然干扰素-1ant在一系列细胞系中刺激了抗病毒活性，但它未能引发免疫调节和抗增殖活性。被测试的各种干扰素的抗病毒活性依赖于一组干扰素敏感基因(“强健”基因)，这些基因由规范的干扰素反应元件控制，并在低浓度的干扰素作用下起反应。相反，在IFN抗增殖反应所需基因(“可调节”基因)的启动子中没有发现这些元件。可调节基因的表达程度因细胞类型而异，并与各种IFN的抗增殖作用的大小相关。虽然干扰素-1ant在五种不同的细胞系中类似地诱导了强健基因的表达，但其抗病毒活性是病毒和细胞类型特异性的。我们的研究结果表明，干扰素-1ant可能是一种治疗特定病毒感染的候选药物，而不会诱导野生型干扰素的免疫调节和抗增殖功能。
Type I interferons (IFNs), including various IFN-α isoforms and IFN-β, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-α2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced binding to IFNAR1. Whereas IFN-1ant stimulated antiviral activity in a range of cell lines, it failed to elicit immunomodulatory and antiproliferative activities. The antiviral activities of the various IFNs tested depended on a set of IFN-sensitive genes (the “robust” genes) that were controlled by canonical IFN response elements and responded at low concentrations of IFNs. Conversely, these elements were not found in the promoters of genes required for the antiproliferative responses of IFNs (the “tunable” genes). The extent of expression of tunable genes was cell type–specific and correlated with the magnitude of the antiproliferative effects of the various IFNs. Although IFN-1ant induced the expression of robust genes similarly in five different cell lines, its antiviral activity was virus- and cell type–specific. Our findings suggest that IFN-1ant may be a therapeutic candidate for the treatment of specific viral infections without inducing the immunomodulatory and antiproliferative functions of wild-type IFN.
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