Stat1-independent induction of SOCS-3 by interferon-γ is mediated by sustained activation of Stat3 in mouse embryonic fibroblasts
Stat1-independent induction of SOCS-3 by interferon-γ is mediated by sustained activation of Stat3 in mouse embryonic fibroblasts
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DOI：
10.1016/j.bbrc.2004.12.074
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发表时间：
2005-02-18
影响因子：
3.1
通讯作者：
Enelow, R
中科院分区：
文献类型：
--
作者：
Ramana, CV;Kumar, A;Enelow, R
利用基因芯片技术，我们先前证明了干扰素-γ在STAT1/-小鼠胚胎成纤维细胞和骨髓来源的巨噬细胞中诱导细胞因子信号转导抑制因子-3(SOCS-3)。在本研究中，我们研究了STAT1非依赖性信号转导通路诱导SOCS-3的机制。酪氨酸激酶JAK1和JAK2是干扰素-γ诱导小鼠胚胎成纤维细胞SOCS-3所必需的。在野生型成纤维细胞中，干扰素-γ刺激STAT1强烈而持续的激活，而STAT3的激活较弱且短暂。相反，STAT3在STAT1-/-成纤维细胞中以持续的方式被强烈激活。在野生型和STAT1-/-成纤维细胞中，Src激酶抑制剂SU6656抑制STAT3的干扰素-γ激活。然而，SU6656完全抑制干扰素-γ对STAT1-/-成纤维细胞SOCS-3的诱导，但对野生型成纤维细胞无此作用。短干扰RNA抑制STAT1/-成纤维细胞中STAT3的激活和干扰素-γ对SOCS-3的诱导作用。在人纤维肉瘤细胞系2fTGH中，干扰素-γ可激活STAT1，但不能激活STAT3。干扰素-γ对SOCS-3的诱导作用是严格依赖STAT1的。干扰素-γ在人肺腺癌细胞中诱导SOCS-3所需的STAT1对接位点。我们提出了一个模型，在该模型中，STAT1或STAT3的持续激活分别介导了干扰素-γ对野生型和STAT1/-小鼠胚胎成纤维细胞SOCS-3的诱导。(C)2004 Elsevier Inc.保留所有权利。
Using microarray technology, we previously demonstrated that IFN-gamma induces suppressor of cytokine signaling-3 (SOCS-3) in Stat1-/- mouse embryonic fibroblasts and bone marrow-derived macrophages. In this study, we have investigated the mechanism by which SOCS-3 is induced by Stat1-independent signal transduction pathway. Tyrosine kinases Jak1 and Jak2 are required for SOCS-3 induction by IFN-gamma in mouse embryonic fibroblasts. IFN-gamma stimulated strong and sustained activation of Stat1 whereas Stat3 activation was weak and transient in wild-type fibroblasts. In contrast, Stat3 is activated strongly and in a sustained manner in Stat1-/- fibroblasts. The Src kinase inhibitor SU6656 suppressed IFN-gamma activation of Stat3 in both wild-type and Stat1-/- fibroblasts. However, SU6656 inhibited IFN-gamma induction of SOCS-3 completely in Stat1-/- but not in wild-type fibroblasts. Knock down of Stat3 by short interfering RNA abrogated Stat3 activation and SOCS-3 induction by IFN-gamma in Stat1-/- fibroblasts. In human fibrosarcoma cell line 2fTGH, IFN-gamma activated Stat1 but not Stat3. SOCS-3 induction by IFN-gamma is strictly Stat1-dependent. The Stat1 docking site is required for SOCS-3 induction by IFN-gamma in human lung adenocarcinoma cells. We propose a model in which sustained activation of Stat1 or Stat3 mediates SOCS-3 induction by IFN-gamma in wild-type and Stat1-/- mouse embryonic fibroblasts, respectively. (C) 2004 Elsevier Inc. All rights reserved.