Persistent interleukin-1β signaling causes long term activation of NFκB in a promoter-specific manner in human glial cells
Persistent interleukin-1β signaling causes long term activation of NFκB in a promoter-specific manner in human glial cells
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DOI：
10.1074/jbc.m509973200
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发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Moynagh, PN
中科院分区：
文献类型：
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作者：
Griffin, BD;Moynagh, PN
核因子 kappa B (NF kappa B) 是一种诱导型转录因子，在调节多种免疫和炎症反应基因的表达中发挥着关键作用。 NF kappa B 的活性在多个水平上受到控制，包括在基础状态下用 kappa B (I kappa B) 蛋白抑制剂保留在细胞质中。在许多慢性炎症疾病状态中都可以看到转录因子的持续激活，我们之前已经证明，在白细胞介素 (IL)-1 β 刺激下，人胶质细胞中 NF kappa B 会持续激活。在这些细胞中，尽管存在重新合成的 I kappa B α 并且不存在 I kappa B beta，NF kappa B 仍保留 DNA 结合活性长达 72 小时。在这里，我们表征了新合成的 I kappa B α 明显无法终止神经胶质细胞中 NF kappa B 的激活。我们出乎意料地发现，新合成的 I kappa B α 可以进入细胞核，与 NF kappa B 亚基 p65 相互作用，并将其输出到细胞质。然而，酶活性的体外分析表明，IL-1β 会引起 IκB 激酶复合物的长期激活，从而导致新合成的 IκBα 信号响应结构域的慢性磷酸化和 NFκB 的持续激活。 NFκB 的持续激活依赖于 IL-1β 的持续存在和活性。有趣的是，NF kappa B 活性的持续性质是启动子类型特异性的。染色质免疫沉淀研究表明，在 IL-1 β 刺激后 1 小时，在细胞间粘附分子 1 和 IL-8 的启动子处均检测到 p65，但仅在 24 小时时才在后者中发现。这一发现的功能意义在于细胞间粘附分子-1 mRNA 的瞬时诱导，但 IL-1 β 更持续地诱导 IL-8 表达。因此，这些研究表明，持续的 IL-1 信号传导导致人神经胶质细胞中 NF kappa B 以启动子特异性方式持续激活，从而导致选择性促炎基因的长期诱导。这可能是导致大脑慢性炎症的一个关键因素。
Nuclear factor-kappa B (NF kappa B) is an inducible transcription factor that plays a key role in regulating the expression of a wide range of immune and inflammatory response genes. The activity of NF kappa B is controlled at multiple levels, including cytoplasmic retention with inhibitor of kappa B (I kappa B) proteins in the basal state. Persistent activation of the transcription factor is seen in numerous chronic inflammatory disease states, and we have previously demonstrated sustained activation of NF kappa B in human glial cells upon stimulation with interleukin (IL)-1 beta. In these cells, NF kappa B retains DNA binding activity for up to 72 h despite the presence of resynthesized I kappa B alpha and in the absence of I kappa B beta. Here we characterized the apparent inability of newly synthesized I kappa B alpha to terminate activation of NF kappa B in glial cells. We showed unexpectedly that newly synthesized I kappa B alpha can enter the nucleus, interact with the NF kappa B subunit p65, and export it to the cytoplasm. However, in vitro analysis of enzyme activity demonstrates that IL-1 beta causes the long term activation of the I kappa B kinase complex leading to chronic phosphorylation of the newly synthesized I kappa B alpha signal response domain and persistent activation of NF kappa B. Such sustained activation of NF kappa B is dependent on the continuous presence and activity of IL-1 beta. Interestingly, the sustained nature of NF kappa B activity is promoter type-specific. Chromatin immunoprecipitation studies revealed that p65 is detected at the promoters of both intercellular adhesion molecule-1 and IL-8 1 h following IL-1 beta stimulation but is only found at the latter at 24 h. The functional significance of this finding is indicated by the transient induction of intercellular adhesion molecule-1 mRNA, but more sustained induction of IL-8 expression, by IL-1 beta. These studies thus demonstrated that persistent IL-1 signaling causes sustained activation of NF kappa B in a promoter-specific manner in human glial cells, leading to prolonged induction of selective pro-inflammatory genes. This is likely to make a key contribution to chronic inflammatory conditions of the brain.