Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappa B
Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappa B
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DOI：
10.1074/jbc.272.23.14899
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发表时间：
1997-06-06
影响因子：
4.8
通讯作者：
Hamilton, TA
中科院分区：
文献类型：
--
作者：
Ohmori, Y;Schreiber, RD;Hamilton, TA
在炎症过程中，干扰素-γ和肿瘤坏死因子-α共同诱导多种基因产物的表达，本文证明这种协同作用部分是由两种不同的转录因子：信号转导和转录激活因子1(STAT1)和核因子-kappaB(NF-kappa B)之间的协同作用所介导的。在正常而不是STAT1缺陷的小鼠成纤维细胞中，干扰素和肿瘤坏死因子α协同诱导编码干扰素调节因子-1(IRF-1)、细胞间黏附分子-1、MIg(由干扰素诱导的单核因子)和RANTES(调节正常T细胞表达和分泌的激活)的mRNAs的表达，这表明需要STAT1。利用IRF-1基因启动子1.3kb序列的定点突变在成纤维细胞中的瞬时转染实验表明，这种协同作用依赖于两个序列元件：STAT结合元件和kappa B基序。含有STAT结合元件和连接到疱疹病毒胸苷激酶启动子的kappa B基序的人工构建物能够介导对干扰素-γ和肿瘤坏死因子-α的协同反应；这种反应因这两个位点之间区域的相对间距和特定序列而异，在由干扰素和/或肿瘤坏死因子α刺激的成纤维细胞核提取液中，协同反应序列结构结合了STAT1α和NF-kappa B，尽管单个因子的结合不是协同的，因此，经常观察到的干扰素和肿瘤坏死因子α在促进炎症反应方面的协同作用部分依赖于STAT1α和NF-kappa B之间的合作，这最有可能是通过它们与基础转录复合体的一个或多个组分的独立相互作用而介导的。
Interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) cooperate to induce the expression of many gene products during inflammation, The present report demonstrates that a portion of this cooperativity is mediated by synergism between two distinct transcription factors: signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kappa B). IFN gamma and TNF alpha synergistically induce expression of mRNAs encoding interferon regulatory factor-1 (IRF-1), intercellular adhesion molecule-1, Mig (monokine induced by gamma-interferon), and RANTES (regulated on activation normal T cell expressed and secreted) in normal but not STAT1-deficient mouse fibroblasts, indicating a requirement for STAT1, Transient transfection assays in fibroblasts using site-directed mutants of a 1.3-kilobase pair sequence of the IRF-1 gene promoter revealed that the synergy was dependent upon two sequence elements; a STAT binding element and a kappa B motif. Artificial constructs containing a single copy of both a STAT binding element and a kappa B motif linked to the herpes virus thymidine kinase promoter were able to mediate synergistic response to IFN gamma and TNF alpha; such response varied with both the relative spacing and the specific sequence of the regions between these two sites, Cooperatively responsive sequence constructs bound both STAT1 alpha and NF-kappa B in nuclear extracts prepared from IFN gamma- and/or TNF alpha-stimulated fibroblasts, although binding of individual factors was not cooperative, Thus, the frequently observed synergy between IFN gamma and TNF alpha in promoting inflammatory response depends in part upon cooperation between STAT1 alpha and NF-kappa B, which is most likely mediated by their independent interaction with one or more components of the basal transcription complex.