The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumour necrosis factor
The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumour necrosis factor
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DOI：
10.1002/j.1460-2075.1996.tb00542.x
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发表时间：
1996-04-15
期刊：
影响因子：
11.4
通讯作者：
Fiers, W
中科院分区：
文献类型：
--
作者：
Beyaert, R;Cuenda, A;Fiers, W
肿瘤坏死因子（TNF）是一种多效性细胞因子，其活性包括对基因表达、细胞生长和细胞死亡的影响。导致这些TNF效应的生物信号机制在很大程度上仍然未知。在这里，我们表明，应激反应p38丝裂原活化蛋白（MAP）激酶参与TNF诱导的细胞因子表达。细胞的TNF处理激活了p38 MAP激酶途径，如通过p38 MAP激酶本身的磷酸化增加、底物蛋白MAPKAP激酶-2的激活以及热休克蛋白27（hsp 27）的磷酸化达到高潮所揭示的。用高度特异性的p38 MAP激酶抑制剂SB 203580预处理细胞完全阻断了TNF诱导的MAPKAP激酶-2和hsp 27磷酸化的激活。在相同的条件下，SB 203580也完全抑制TNF诱导的白细胞介素（IL）-6的合成和由含有两个NF-κ B元件的最小启动子驱动的报告基因的表达。然而，无论是TNF-诱导的DNA结合NF-κ B，也没有TNF-诱导的磷酸化的亚基调节SB 203580，表明NF-κ B是不是一个直接的目标为p38 MAP激酶途径。有趣的是，TNF诱导的细胞毒性不受SB 203580的影响，表明p38 MAP激酶可能是一个有趣的目标，选择性干扰TNF诱导的基因激活。
Tumour necrosis factor (TNF) is a pleiotropic cytokine, the activities of which include effects on gene expression, cell growth and cell death. The biological signalling mechanisms which are responsible for these TNF effects remain largely unknown. Here we demonstrate that the stress-responsive p38 mitogen-activated protein (MAP) kinase is involved in TNF-induced cytokine expression. TNF treatment of cells activated the p38 MAP kinase pathway, as revealed by increased phosphorylation of p38 MAP kinase itself, activation of the substrate protein MAPKAP kinase-2, and culminating in the phosphorylation of the heat shock protein 27 (hsp27). Pretreatment of cells with the highly specific p38 MAP kinase inhibitor SB203580 completely blocked this TNF-induced activation of MAPKAP kinase-2 and hsp27 phosphorylation. Under the same conditions, SB203580 also completely inhibited TNF-induced synthesis of interleukin (IL)-6 and expression of a reporter gene that was driven by a minimal promoter containing two NF-kappa B elements. However, neither TNF-induced DNA binding of NF-kappa B nor TNF-induced phosphorylation of its subunits was modulated by SB203580, suggesting that NF-kappa B is not a direct target for the p38 MAP kinase pathway. Interestingly, TNF-induced cytotoxicity was not affected by SB203580, indicating that p38 MAP kinase might be an interesting target to interfere selectively with TNF-induced gene activation.