TRIGGERING OF THE HUMAN INTERLEUKIN-6 GENE BY INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA IN MONOCYTIC CELLS INVOLVES COOPERATION BETWEEN INTERFERON REGULATORY FACTOR-I, NF-KAPPA-B, AND SP1 TRANSCRIPTION FACTORS
TRIGGERING OF THE HUMAN INTERLEUKIN-6 GENE BY INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA IN MONOCYTIC CELLS INVOLVES COOPERATION BETWEEN INTERFERON REGULATORY FACTOR-I, NF-KAPPA-B, AND SP1 TRANSCRIPTION FACTORS
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DOI：
10.1074/jbc.270.46.27920
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发表时间：
1995-11-17
影响因子：
4.8
通讯作者：
WIETZERBIN, J
中科院分区：
文献类型：
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作者：
SANCEAU, J;KAISHO, T;WIETZERBIN, J
我们研究了干扰素-γ(干扰素-γ)/肿瘤坏死因子-α(TNF-α)协同诱导人白介素6(IL-6)基因对THP-1单核细胞作用的分子基础，并在此基础上与脂多糖(LPS)进行了比较。IL-6启动子的功能研究表明，有三个区域是干扰素-γ和/或肿瘤坏死因子-α作用的靶点，而这三个区域中似乎只有一个参与了内毒素的激活，涉及的三个区域是：1)介于-73和-36之间的区域；这是内毒素或肿瘤坏死因子-α诱导的最低限度的元素；2)位于-181和-73之间的元件，它似乎负向调节对干扰素-γ和肿瘤坏死因子-α的反应；以及3)位于-224上游的一个远端元件，它可以单独被干扰素-γ诱导。内毒素信号转导涉及p50/p65异源二聚体激活Mf-kappa B。在单核细胞中，干扰素-γ和肿瘤坏死因子-α协同诱导IL-6基因，包括IRF-1和NF-kappa B p65同源二聚体之间的协同作用，同时去除存在于IL-6启动子中的视网膜母细胞瘤控制元件的负面影响。这种去除是通过激活构成的Sp1因子来实现的，其结合活性和磷酸化的增加是由干扰素-γ介导的。
We investigated the molecular basis of the synergistic induction by iterferon-gamma (IFN-gamma)/tumor necrosis factor-alpha (TNF-alpha) of human interleukin-6 (IL-6) gene in THP-1 monocytic cells, and compared it with the basis of this induction by lipopolysaccharide (LPS), Functional studies with IL-6 promoter demonstrated that three regions are the targets of the IFN-gamma and/or TNF-gamma action, whereas only one of these regions seemed to be implicated in LPS activation, The three regions concerned are: 1) a region between -73 and -36, which is the minimal element inducible by LPS or TNF-alpha; 2) an element located between -181 and -73, which appeared to regulate the response to IFN-gamma and TNF-alpha negatively; and 3) a distal element upstream of -224, which was inducible by IFN-gamma alone. LPS signaling was found to involve MF kappa B activation by the p50/p65 heterodimers. Synergis tic induction of the IL-6 gene by IFN-gamma and TNF-alpha, in monocytic cells, involved cooperation between the IRF-1 and NF kappa B p65 homodimers with concomitant removal of the negative effect of the retinoblastoma control element present in the IL-6 promoter. This removal occurred by activation of the constitutive Sp1 factor, whose increased binding activity and phosphorylation were mediated by IFN-gamma.