Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6
Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6
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DOI：
10.1016/s0006-2952(00)00412-3
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发表时间：
2000-10-15
影响因子：
5.8
通讯作者：
Haegeman, G
中科院分区：
文献类型：
--
作者：
Vanden Berghe, W;Vermeulen, L;Haegeman, G
白介素6(IL-6)是一种多功能的细胞因子，可被大量的化学或生理化合物诱导，包括炎性细胞因子肿瘤坏死因子(TNF)和IL-1。肿瘤坏死因子分子具有三聚体构型，因此与膜结合的细胞受体结合，启动细胞死亡机制和信号通路，导致基因诱导。以前，我们已经证明，诱导P55肿瘤坏死因子受体的胞内域的聚集，或仅诱导它们各自的死亡结构域的聚集，足以激活核因子kappa B(NF-kappa B)和几个丝裂原激活的蛋白激酶(MAPK)途径。核因子-kappaB是诱导IL-6基因应答肿瘤坏死因子的唯一转录因子，是在IL-6启动子水平上激活多蛋白复合体的最终触发器。此外，增强体表现出组蛋白乙酰化活性，这是通过核因子-kappaB激活IL-6基因所必需的。然而，单独激活核因子-kappa B不足以诱导IL-6基因对肿瘤坏死因子的应答，因为共激活的细胞外信号调节激酶和p38MAPK通路的抑制阻断了肿瘤坏死因子介导的基因表达。然而，反式激活的核因子-kappaB亚单位p65并不是MAPK磷酸化的直接靶点。因此，我们推测增强体复合体的其他成分对MAPK级联反应敏感，并发现MAPK活性明确地与增强体的组蛋白乙酰化能力有关，以刺激基因表达以响应肿瘤坏死因子。相反，糖皮质激素对肿瘤坏死因子诱导的IL-6基因表达的抑制并不依赖于组蛋白乙酰转移酶活性的降低，而是源于连接的糖皮质激素受体干扰了核因子-kappa B p65与TATA盒周围的启动子构型之间的接触。Biochem Pharmacol 60；8：1185-1195,2000。(C)2000年爱思唯尔科学公司。
Interleukin (IL)-6 is a multifunctional cytokine that can be induced by a plethora of chemical or physiological compounds, including the inflammatory cytokines tumor necrosis factor (TNF) and IL-1. The molecule TNF has a trimeric configuration and thus binds to membrane-bound, cellular receptors to initiate cell death mechanisms and signaling pathways leading to gene induction. Previously, we showed that induced clustering of the intracellular domains of the p55 TNF receptor, or of their respective 'death domains' only, is sufficient to activate the nuclear factor kappa B (NF-kappa B) and several mitogen-activated protein kinase (MAPK) pathways. NF-kappa B is the exclusive transcription factor for induction of the IL-6 gene in response to TNF and functions as the final trigger to activate a multiprotein complex, a so-called 'enhanceosome', at the level of the IL-6 promoter. Furthermore, the enhanceosome displays histone acetylation activity, which turned out to be essential for IL-6 gene activation via NF-kappa B. However, activation of NF-kappa B alone is not sufficient for IL-6 gene induction in response to TNF, as inhibition of the coactivated extracellular signal-regulated kinase and p38 MAPK pathways blocks TNF-mediated gene expression. Nevertheless, the transactivating NF-kappa B subunit p65 is not a direct target of MAPK phosphorylation. Thus, we postulated that other components of the enhanceosome complex are sensitive to MAPK cascades and found that MAPK activity is unequivocally linked to the histone acetylation capacity of the enhanceosome to stimulate gene expression in response to TNF. In contrast, glucocorticoid repression of TNF-driven IL-6 gene expression does not depend on abrogation of histone acetyltransferase activity, hut originates from interference of the liganded glucocorticoid receptor with the contacts between NF-kappa B p65 and the promoter configuration around the TATA box. BIOCHEM PHARMACOL 60;8:1185-1195, 2000. (C) 2000 Elsevier Science Inc.