ERK and p38 MAP kinase are involved in downregulation of cell surface TNF receptor 1 induced by acetoxycycloheximide
ERK and p38 MAP kinase are involved in downregulation of cell surface TNF receptor 1 induced by acetoxycycloheximide
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DOI：
10.1016/j.intimp.2008.02.010
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发表时间：
2008-06-01
影响因子：
5.6
通讯作者：
Kataoka, Takao
中科院分区：
文献类型：
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作者：
Ogura, Hirotsugu;Tsukumo, Yoshinori;Kataoka, Takao
肿瘤坏死因子(TNF)- α激活核因子κ B （nf - κ B）信号通路。蛋白质合成抑制剂环己亚胺（CHX）及其结构衍生物乙酰氧基环己亚胺（Ac-CHX）最近在人肺癌A549细胞中被证明可以通过TNF受体1 （TNF- r1）的外域脱落来阻断TNF- α诱导的NF-kappa B的激活。在这项研究中，我们发现ERK和p38 MAP激酶参与了暴露于Ac-CHX后细胞表面TNF-R1的下调以及随后tnf - α诱导的NF-kappa B活化的抑制。Ac-CHX能够促进ERK、JNK和p38 MAP激酶的持续激活。在ac - chx处理的细胞中，MEK抑制剂U0126和p38 MAP激酶抑制剂SB203580，而不是JNK抑制剂SP600125，逆转了细胞表面TNF-R1表达的减少以及tnf -a诱导的I κ B α降解的阻断。我们的研究结果表明，Ac-CHX通过激活ERK和p38 MAP激酶触发细胞表面TNF-R1的下调，从而阻止tnf - α激活NF-kappa B信号通路。(C) 2008 Elsevier B.V.版权所有
Tumor necrosis factor (TNF)-alpha activates the nuclear factor kappa B (NF-kappa B) signaling pathway. The protein synthesis inhibitor cycloheximide (CHX) and its structural derivative acetoxycycloheximide (Ac-CHX) have been recently shown to block the TNF-alpha-induced activation of NF-kappa B via ectodomain shedding of TNF receptor 1 (TNF-R1) in human lung carcinoma A549 cells. In this study, we show that ERK and p38 MAP kinase are involved in the downregulation of cell surface TNF-R1 upon exposure to Ac-CHX and the subsequent inhibition of TNF-alpha-induced NF-kappa B activation. Ac-CHX was capable of promoting the sustained activation of ERK, JNK, and p38 MAP kinase. Treatment with the MEK inhibitor U0126 and the p38 MAP kinase inhibitor SB203580, but not the JNK inhibitor SP600125, reversed the diminished expression of cell surface TNF-R1 as well as the blockade of TNF-a-induced I kappa B alpha degradation in Ac-CHX-treated cells. Our results indicate that Ac-CHX triggers the downregulation of cell surface TNF-R1 via the activation of ERK and p38 MAP kinase, thereby preventing activation of the NF-kappa B signaling pathway by TNF-alpha. (C) 2008 Elsevier B.V. All rights reserved.