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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.

Santonin 相关化合物 (SRC) 以起始材料 L-α-santonin 为原料合成，并测试了 ICAM-1 在炎症细胞因子 IL-1 刺激下表达的生物活性。 SRC2 是一种溴酮衍生物，不含 α-亚甲基-γ-内酯，可强烈抑制 IL-1 诱导的 ICAM-1 表达。 SRC2 阻止了 NF-κB 的核转位和 IκB 降解，表明 SRC2 阻断了 IκB 降解上游的 IL-1 信号通路。放线菌酮的结构类似物 E-73（乙酰氧基放线菌酮）被发现可以特异性抑制 TNF 诱导的 ICAM-1 表达。 E-73 显着阻止了 TNF（而非 IL-1）诱导的 NF-κB 核转位以及 IκB 降解。 p38 MAP激酶的激活似乎参与了E-73对TNF诱导的NF-κB激活的抑制作用。霉菌毒素青霉酸抑制Fas配体诱导的细胞凋亡。青霉酸显着阻断 DISC 中 caspase-8 的自裂解，但不影响 Fas 配体诱导的 DISC 形成。在无细胞系统中，青霉酸抑制细胞色素 C 诱导的 caspase-9 活化，但该毒素不抑制活化的 caspase-3。因此，青霉酸似乎通过阻止 caspase-8 和 -9 等起始 caspase 的自我裂解来靶向它们。在重组 Fas 配体增加 CD3 激活的人外周 T 淋巴细胞增殖的条件下，转录因子 NF-κB 和 AP-1 被激活，并且 caspase-8 抑制剂 FLIP 募集到 DISC 中。FLIP 相互作用与接头蛋白 TRAF-1、TRAF-2、激酶 RIP、MAKKK Raf-1 结合，导致 NF-κB 和 Erk 信号通路的激活。在 T 细胞中，FLIP 似乎与 T 细胞受体的刺激协同作用，从而增强 NF-κB 和 Erk 激活，导致 IL-2 的产生增加。