Bartee Eric, Mohamed Mohamed R, Lopez M Cecilia, Baker Henry V, McFadden Grant
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
J Virol. 2009 Jan;83(2):498-511. doi: 10.1128/JVI.01376-08. Epub 2008 Oct 29.
Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-beta induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-beta induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone.
肿瘤坏死因子（TNF）和干扰素（IFN）家族成员已被证明可独立抑制多种病毒的复制。此外，先前的报道表明，用这些抗病毒细胞因子的各种组合进行治疗可诱导一种协同抗病毒状态，这种状态可能比单独添加任何一种细胞因子的效果显著更强。然而，这种细胞因子协同作用的机制及其对整体基因表达的影响尚未得到充分表征。在这里，我们使用DNA微阵列分析来证明，用TNF加IFN-β处理未感染的原代人成纤维细胞会诱导一种独特的协同状态，其特征是数百个基因受到显著干扰，这些基因单独由单个细胞因子共同诱导，同时还诱导了850多个新的宿主细胞基因。这种协同作用直接由两种配体介导，而不是由中间分泌因子介导，并且对于完全阻断黏液瘤病毒在人成纤维细胞中的有效复制和传播是必要且充分的。相比之下，另外两种痘病毒，痘苗病毒和塔纳痘病毒的复制在这些细胞中仅被协同抗病毒状态部分抑制，而这两种病毒向邻近细胞的传播则被有效阻断。综上所述，我们的数据表明，TNF和IFN-β的组合诱导了一种新型的协同抗病毒状态，该状态与单独由任何一种细胞因子诱导的状态高度不同。
