Mutational switch of an IL-6 response to an interferon-γ-like response
Mutational switch of an IL-6 response to an interferon-γ-like response
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DOI：
10.1073/pnas.122236099
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发表时间：
2002-06-11
影响因子：
11.1
通讯作者：
Poli, V
中科院分区：
文献类型：
--
作者：
Costa-Pereira, AP;Tininini, S;Poli, V
通过Janus激酶（JAKs）和信号转导和转录激活因子（STATs）的信号传导是对大多数细胞因子和一些生长因子（包括干扰素（IFNs）和细胞因子IL-6家族）的反应的核心。然而，通过广泛分布的IL-6和ifn - γ受体对刺激的生物学反应是完全不同的。值得注意的是，在缺乏STAT3的小鼠胚胎成纤维细胞中，IL-6介导ifn - γ样反应，包括STAT1的长时间激活、诱导多种ifn - γ诱导基因、II类MHC抗原的表达和抗病毒状态。因此，暴露于IL-6的正常细胞需要stat3依赖功能来下调STAT1活性并防止ifn - γ样反应。这些数据支持这样一种观点，即非常不同的ifn - γ和IL-6 JAK/受体复合物介导一组共同的通用或“核心”信号，这些信号受stat3依赖性调节以提供IL-6特异性。由于单个信号成分的缺失，一种细胞因子的反应转变为另一种细胞因子的反应，这具有深远的意义，例如，对于基因敲除小鼠的表型解释和信号传导抑制剂的临床使用。
Signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) is central to the responses to the majority of cytokines and some growth factors, including the interferons (IFNs) and the IL-6 family of cytokines. The biological responses to stimulation through the widely distributed IL-6 and IFN-gamma receptors are, however, completely different. Remarkably, it is shown here that, in mouse embryo fibroblasts lacking STAT3, IL-6 mediates an IFN-gamma-like response including prolonged activation of STAT1, the induction of multiple IFN-gamma-inducible genes, the expression of class II MHC antigens, and an antiviral state. Normal cells exposed to IL-6 thus require a STAT3-dependent function(s) to down-regulate STAT1 activity and prevent an IFN-gamma-like response. The data encourage the view that the very disparate IFN-gamma and IL-6 JAK/receptor complexes mediate a common set of generic or "core" signals which are subject to STAT3-dependent modulation to provide IL-6 specificity. The switching of one cytokine response to one closely mimicking another as a result of the loss of a single signaling component has profound implications, for example, for the interpretation of the phenotypes of knockout mice and for the clinical use of inhibitors of signaling.