SYNERGISTIC INTERACTION BETWEEN INTERFERON-ALPHA AND INTERFERON-GAMMA THROUGH INDUCED SYNTHESIS OF ONE SUBUNIT OF THE TRANSCRIPTION FACTOR ISGF3
SYNERGISTIC INTERACTION BETWEEN INTERFERON-ALPHA AND INTERFERON-GAMMA THROUGH INDUCED SYNTHESIS OF ONE SUBUNIT OF THE TRANSCRIPTION FACTOR ISGF3
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DOI：
10.1002/j.1460-2075.1990.tb08216.x
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发表时间：
1990-04-01
期刊：
影响因子：
11.4
通讯作者：
DARNELL, JE
中科院分区：
文献类型：
--
作者：
LEVY, DE;LEW, DJ;DARNELL, JE
干扰素-.alpha。（ifn . α）和干扰素- γ（ifn . γ .）每一种都在易感靶细胞中诱导一种抵抗病毒复制和减少细胞增殖的状态，可能是通过不同的机制：这两种多肽在初级序列上是不相关的，它们通过不同的细胞表面受体作用，诱导大量不重叠的基因集的表达。然而，协同行动，他们可以产生协同作用，导致相互加强的生理反应。在HeLa细胞中，这种协同反应是由ifn . α的协同诱导启动的。受刺激基因（isg）。这些通常处于静止状态的基因在细胞暴露于ifn . α后被迅速诱导到高转录率。尽管它们对干扰素γ的反应微不足道。与ifn . γ联合治疗细胞。然后是IFN.alpha。结果是。apprx。ISG转录增加10倍。ISG转录依赖于ISGF3， ISGF3是ISG启动子中顺式调控元件特异性的阳性转录因子。IFN.gamma。治疗诱导潜在的ISGF3合成增加，随后在ifn . α的作用下被激活。形成。apprx。比用ifn处理的细胞中检测到的水平高10倍。独自一人。ISGF3由两种不同的多肽组分组成，其中一种的合成是由ifn . γ诱导的。将其细胞丰度从限制浓度增加到允许形成至少10倍的活性ISGF3的水平。细胞系在ISGF3诱导成分的组成水平和ifn增加其合成的能力方面各不相同。协同诱导细胞因子特异性转录因子是一种产生不同细胞表面配体增强效应的机制，同时仍保持单个诱导剂的特异性。
Interferon-.alpha. (IFN.alpha.) and interferon-.gamma. (IFN.gamma.) each induce in susceptible target cells a state of resistance to viral replication and reduced cellular proliferation, presumably through different mechanisms: these two polypeptides are unrelated by primary sequence and act through distinct cell-surface receptors to induce expression of largely non-overlapping sets of genes. However, acting in concert, they can produce synergistic interactions leading to mutual reinforcement of the physiological response. In HeLa cells, this synergistic response was initiated by cooperative induction of IFN.alpha. stimulated genes (ISGs). These normally quiescent genes were rapidly induced to high rates of transcription following exposure of cells to IFN.alpha.. Although they were only negligibly responsive to IFN.gamma., combined treatment of cells with IFN.gamma. followed by IFN.alpha. resulted in an .apprx. 10-fold increase in ISG transcription. ISG transcription is dependent upon ISGF3, a positive transcription factor specific for a cis-acting regulatory element in ISG promoters. IFN.gamma. treatment induced increased synthesis of latent ISGF3, which was subsequently activated in response to IFN.alpha. to form .apprx. 10-fold higher levels than detected in cells treated with IFN.alpha. alone. ISGF3 is composed of two distinct polypeptide components, synthesis of one of which was induced by IFN.gamma., increasing its cellular abundance from limiting concentrations to a level which allowed formation of at least 10 times as much active ISGF3. Cell lines vary in their constitutive levels of the inducible component of ISGF3 and in the ability of IFNs to increase its synthesis. The cooperative induction of cytokine-specific transcription factors is one mechanism for producing reinforcing effects of distinct cell-surface ligands while still maintaining the specificities of the individual inducers.