High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells.
High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells.
复制标题
高基底STAT4通过STAT1诱导在天然杀伤细胞中控制1型干扰素效应。
DOI：
10.1084/jem.20070401
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发表时间：
2007-10-01
影响因子：
15.3
通讯作者：
Biron, Christine A
中科院分区：
文献类型：
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作者：
Miyagi, Takuya;Gil, M Pilar;Wang, Xin;Louten, Jennifer;Chu, Wen-Ming;Biron, Christine A
最具特征的1型干扰素（IFN）信号通路依赖于信号换能器和转录激活因子1 （STAT1）和STAT2。然而，细胞因子可以有条件地激活所有stat。它们进入特定信号通路的调控机制尚不清楚。STAT4对IFN-γ的诱导很重要，而NK细胞是这种细胞因子的主要产生者。我们报道NK细胞具有高基础STAT4水平和对1型IFN介导的STAT4激活IFN-γ产生的敏感性。在病毒感染期间，由1型IFN或IFN-γ驱动的STAT1增加与STAT4通路减少相关。STAT1和STAT2对抗病毒防御都很重要，但STAT1在防止NK细胞持续产生IFN-γ和由此引起的疾病方面具有独特的作用。这种调节发生在NK细胞1型IFN受体从STAT4转换到STAT1关联时。因此，NK细胞的一个基本特征是与1型IFN受体结合的高STAT4。感染条件导致STAT1诱导，STAT4移位。这些研究阐明了STAT4水平在特定信号通路易感性选择中的关键作用，定义了特定细胞系中调控的生物学重要性，并提供了如何在体内完成这一过程的机制见解。
The best-characterized type 1 interferon (IFN) signaling pathway depends on signal transducer and activator of transcription 1 (STAT1) and STAT2. The cytokines can, however, conditionally activate all STATs. Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-γ induction, and NK cells are major producers of this cytokine. We report that NK cells have high basal STAT4 levels and sensitivity to type 1 IFN–mediated STAT4 activation for IFN-γ production. Increases in STAT1, driven during viral infection by either type 1 IFN or IFN-γ, are associated with decreased STAT4 access. Both STAT1 and STAT2 are important for antiviral defense, but STAT1 has a unique role in protecting against sustained NK cell IFN-γ production and resulting disease. The regulation occurs with an NK cell type 1 IFN receptor switch from a STAT4 to a STAT1 association. Thus, a fundamental characteristic of NK cells is high STAT4 bound to the type 1 IFN receptor. The conditions of infection result in STAT1 induction with displacement of STAT4. These studies elucidate the critical role of STAT4 levels in predisposing selection of specific signaling pathways, define the biological importance of regulation within particular cell lineages, and provide mechanistic insights for how this is accomplished in vivo.