Analysis of apoptosis induction and NF-κB activation mediated by death receptors

死亡受体介导的细胞凋亡诱导和 NF-κB 激活分析

基本信息

批准号：
11660077
负责人：
KATAOKA Takao
金额：
$ 2.24万
依托单位：
Tokyo Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11660077/
关键词：
Fas TNF NF-κB E-73 p38 MAP kinase Penicillic acid Caspase FLIP Death receptor NF-kB Caspase-8 ICAM-1 SRC2 E73

项目摘要

Santonin-related compounds (SRCs) were synthesized from the starting material L-α-santonin and tested for the biological activity on the expression of ICAM-1 in response to stimulation with the inflammatory cytokine IL-1. SRC2, one of the bromoketone derivatives, devoid of α-methylene-γ-lactone strongly inhibited the IL-1-induced ICAM-1 expression. The nuclear translocation of NF-κB and the IκB degradation were prevented by SRC2, suggesting that SRC2 blocks the IL-1 signaling pathway upstream of the IκB degradation. A close structural analogue of cycloheximide, E-73 (acetoxycycloheximide) was found to specifically inhibit TNF-induced ICAM-1 expression. The nuclear translocation of NF-κB as well as the IκB degradation induced by TNF, but not IL-1, were markedly prevented by E-73. Activation of p38 MAP kinase seems to be involved in the inhibitory effect of E-73 on the TNF-induced NF-κB activation.The mycotoxin penicillic acid inhibited apoptosis induced by Fas ligand. Penicillic acid significantly blocked self-cleavage of caspase-8 in the DISC, although it did not influence Fas ligand-induced DISC formation. In the cell-free system, cytochrome C-induced caspase-9 activation was inhibited by penicillic acid, although the toxin did not inhibit activated caspase-3. Thus, penicillic acid seems to target iniciator caspases such as caspase-8 and -9 by preventing their self-cleavage.Under conditions in which proliferation of CD3-activated human peripheral T lymphocytes is increased by recombinant Fas ligand, there was activation of the transcription factor NF-κB and AP-1 and recruitment of the caspase-8 inhibitor FLIP into the DISC.FLIP interacted with the adaptor proteins TRAF-1, TRAF-2, the kinase RIP, MAKKK Raf-1, resulting in the activation of NF-κB and Erk signaling pathways. In T cells FLIP seems to act cooperatively with stimulation through T cell receptors and thereby augment NF-κB and Erk activation, leading to increased production of IL-2.

从起始材料L-α-抗肽合成了与Santonin相关的化合物（SRC），并测试了ICAM-1表达的生物学活性，以响应炎症细胞因子IL-1刺激。 SRC2是溴酮衍生物之一，没有α-甲基-γ-乳酮强烈抑制IL-1诱导的ICAM-1表达。 SRC2阻止了NF-κB和IκB降解的核转运，这表明SRC2阻止了IκB降解上游的IL-1信号通路。发现环己酰亚胺，E-73（乙酰氧基己酰胺）的紧密结构类似物特异性抑制了TNF诱导的ICAM-1表达。 E-73明显阻止了NF-κB的核转运以及由TNF而非IL-1引起的IκB降解。 p38 MAP激酶的激活似乎参与E-73对TNF诱导的NF-κB激活的抑制作用。 FAS配体诱导的霉菌毒素青霉酸抑制了凋亡。椎间盘中caspase-8显着阻断了caspase-8的自切除，尽管它不影响FAS配体诱导的椎间盘形成。在无细胞系统中，尽管毒素没有抑制活化的caspase-3，但细胞色素c诱导的caspase-9激活受到了青霉酸的抑制。这是，通过防止其自我切割来靶向造成孔caspase（例如caspase-8和-9）的靶向孔壳。衔接蛋白TRAF-1，TRAF-2，激酶RIP，Makkk RAF-1，导致NF-κB和ERK信号通路的激活。在T细胞中，翻转似乎通过T细胞受体刺激起作用，从而增加NF-κB和ERK激活，从而导致IL-2的产生增加。