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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.

以L-α-山道宁为起始原料合成了山道宁相关化合物（SRCs），并检测了其对炎症细胞因子IL-1刺激后ICAM-1表达的生物活性。SRC 2是一种不含α-亚甲基-γ-内酯的溴代酮衍生物，可强烈抑制IL-1诱导的ICAM-1表达。SRC 2抑制了NF-κB的核转位和IκB的降解，表明SRC 2阻断了IκB降解上游的IL-1信号通路。发现放线菌酮的一种结构类似物E-73（乙酰氧基放线菌酮）特异性抑制TNF诱导的ICAM-1表达。E-73可显著抑制TNF诱导的NF-κB核转位和IκB降解，但对IL-1无影响。E-73抑制TNF-α诱导的NF-κB活化可能与激活p38 MAP激酶有关，真菌毒素青霉素酸抑制Fas配体诱导的细胞凋亡。青霉酸显着阻断自切割的caspase-8的DISC，虽然它没有影响Fas配体诱导的DISC的形成。在无细胞系统中，细胞色素C诱导的半胱天冬酶-9活化抑制青霉酸，虽然毒素不抑制活化的半胱天冬酶-3。在重组Fas配体促进CD 3激活的人外周血T淋巴细胞增殖的条件下，转录因子NF-κB和AP-1被激活，caspase-8抑制剂FLIP被募集到DISC中。FLIP与衔接蛋白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，FLIP似乎通过T细胞受体与刺激协同作用，从而增强NF-κB和Erk活化，导致IL-2产生增加。