ERK and p38 MAP kinase are involved in downregulation of cell surface TNF receptor 1 induced by acetoxycycloheximide
- 作者：Hirotsugu Ogura ; Yoshinori Tsukumo ; Hikaru Sugimoto ; Masayuki Igarashi ; Kazuo Nagai ; Takao Kataoka
- 关键词：Acetoxycycloheximide ; ERK ; NF-κ ; B ; p38 MAP kinase ; TNF receptor 1
- 刊名：International Immunopharmacology
- 出版年：2008
- 期刊代码：123_15675769
- 类别：med
- 出版时间：June 2008
- 卷：8
- 期：6
- 页码：922-926
- 文件大小：568 K
摘要
Tumor necrosis factor (TNF)-
activates the nuclear factor κB (NF-κB) signaling pathway. The protein synthesis inhibitor cycloheximide (CHX) and its structural derivative acetoxycycloheximide (Ac-CHX) have been recently shown to block the TNF--induced activation of NF-κB 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--induced NF-κB 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--induced IκB 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-κB signaling pathway by TNF-.
activates the nuclear factor κB (NF-κB) signaling pathway. The protein synthesis inhibitor cycloheximide (CHX) and its structural derivative acetoxycycloheximide (Ac-CHX) have been recently shown to block the TNF--induced activation of NF-κB 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--induced NF-κB 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--induced IκB 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-κB signaling pathway by TNF-.