Inhibition of ceramide pathway does not affect ability of TNF-alpha to activate nuclear factor-kappa B.
Inhibition of ceramide pathway does not affect ability of TNF-alpha to activate nuclear factor-kappa B.
复制标题
神经酰胺途径的抑制不影响 TNF-α 激活核因子-κ B 的能力。
DOI：
10.4049/jimmunol.152.12.5877
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发表时间：
1994
影响因子：
4.4
通讯作者：
G. Ranges
中科院分区：
文献类型：
--
作者：
L. D. Johns;T. Sarr;G. Ranges
tnf - α是一种多功能细胞因子，已被证明可激活许多细胞内第二信使途径。最近的研究表明鞘磷脂酶-神经酰胺途径在tnf - α活化核因子κ B （nf - κ B）中起潜在作用。下面的实验都证实了在细胞中添加神经酰胺可以激活NF-kappa B，并证明了用12-肉豆蔻酸佛波酯（PMA）预处理48小时会导致神经酰胺诱导的NF-kappa B反应丧失。在平行实验中，用PMA预处理SW480细胞，tnf - α提供的信号导致nf - κ B的核易位，与未处理的细胞相似。这些数据综合起来表明，存在TNF- α可用于激活NF-kappa B的其他途径。补充数据表明，TNF- α、神经酰胺和PMA激活人巨细胞病毒(HCMV) β - gal构建子（启动子对NF-kappa B有反应），该构建子被稳定地转染到携带TNF受体的肿瘤细胞系SW480中。PMA预处理这些细胞导致PMA和神经酰胺产生的反应显著下降，分别为对照组的6%和0%。然而，由tnf - α产生的反应没有被明显抑制（96%的对照细胞）。这些数据表明，尽管神经酰胺和1,2-二酰基甘油（DAG）途径可能有助于tnf - α激活NF-kappa B，但这些途径的阻抗不会阻止tnf - α激活NF-kappa B，也不会诱导NF-kappa B应答性报告结构HCMV的功能激活。
TNF-alpha is a multifunctional cytokine that has been shown to activate a number of intracellular second messenger pathways. Recent studies demonstrate that the sphingomyelinase-ceramide pathway plays a potential role in the activation of nuclear factor-kappa B (NF-kappa B) by TNF-alpha. The following experiments both confirm that the addition of ceramide to cells can activate NF-kappa B and demonstrate that a 48-h pretreatment with phorbol 12-myristate (PMA) results in the loss of the ceramide-induced NF-kappa B response. In parallel experiments, in which SW480 cells were pretreated with PMA, TNF-alpha provided a signal resulting in the nuclear translocation of NF-kappa B that was similar to untreated cells. These data combined suggest that additional pathways exist that TNF-alpha can use for the activation of NF-kappa B. Supplementary data demonstrates that TNF-alpha, ceramide, and PMA activate a human cytomegalovirus-(HCMV) beta gal construct (promoter is responsive to NF-kappa B) that was stably transfected into the TNF receptor-bearing tumor cell line, SW480. PMA pretreatment of these cells resulted in a significant decrease in both the PMA and ceramide generated responses, 6% and 0% of controls, respectively. However, the response generated by TNF-alpha was not inhibited significantly (96% of control cells). This data suggests that although ceramide and 1,2-diacylglycerol (DAG) pathways may contribute to TNF-alpha activation of NF-kappa B, impedance of these pathways does not block TNF-alpha from activating NF-kappa B nor induction of the functional activation of the NF-kappa B responsive reporter construct, HCMV.