NF-κ B mediated apoptosis induced by TNF/IFN-α

NF-κB 介导 TNF/IFN-α 诱导的细胞凋亡

• 批准号: 12671228
• 负责人: HAISA Minoru
• 金额: $ 1.02万
• 依托单位: Okayama University Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671228/
• 关键词: cytokine cross-talk; apoptosis; NF-κB; TNF; IFN-α; Fas; NF-kB; TNF-α

Recently, we reported that TNF/IFN-α combined treatment inhibited the in vitro and in vivo proliferation of human colon adenocarcinoma cells. Immunostaining and EMSA revealed that NF-κB was activated strongly by TNF/IFN-α compared to TNF alone in a human colon adenocarcinoma cell line, RPMI4788. Although inhibition of activated NF-κB, by using a NF-κB decoy, reduced cell viability after treatment with TNF only, NF-κB decoy resulted in recovery of cell viability after TNF/IFN-α treatment. Caspase-3 activity was increased in cells induced by TNF/IFN-α, while suppression of caspase-3 activity was observed in cells transfected with NF-κB decoy and then treated by TNF/IFN-α. On the other hand, Fas expression was strongly enhanced by TNF/IFN-α, and inhibition of TNF/IFN-α-induced NF-κB activation, by using NF-κB decoy, decreased Fas expression. Cell viability and caspase-3 activity decreased in cells treated with TNF/IFN-α and anti-FasL antibody. Taken together, our findings suggest that activated NF-κB induced by the cross-talk between TNF and IFN-α is a novel pro-apoptotic signal acting via enhancement of Fas expression. Our observations provide the first evidence in carcinoma cells indicating that TNF-induced NF-κB activation, which has an anti-apoptotic function, may be modified to a pro-apoptotic function by cytokine cross-talk between TNF and IFN-α. Such actions might be of clinicopharmacological value, where apoptosis of tumor cells could be efficiently induced by TNF/IFN-α and FasL, or up-regulators of FasL in combination might become a clinically applicable new strategy in cancer therapy.

最近，我们报道了TNF/IFN-α联合应用抑制人结肠腺癌细胞的体内外增殖。免疫染色和EMSA显示，在人结肠腺癌细胞系RPMI 4788中，与单独TNF相比，TNF/IFN-α强烈激活NF-κB。虽然通过使用NF-κB诱饵抑制活化的NF-κB，在仅用TNF处理后降低细胞活力，但NF-κB诱饵导致TNF/IFN-α处理后细胞活力的恢复。TNF/IFN-α诱导的细胞Caspase-3活性升高，而转染NF-κB decoy后再经TNF/IFN-α处理的细胞Caspase-3活性降低。另一方面，TNF/IFN-α可显著增强Fas的表达，用NF-κB诱饵抑制TNF/IFN-α诱导的NF-κB活化，可降低Fas的表达。TNF/IFN-α和抗FasL抗体处理的细胞活力和caspase-3活性降低。综上所述，我们的研究结果表明，激活NF-κB诱导的TNF和IFN-α之间的串扰是一种新的促凋亡信号，通过增强Fas的表达。我们的观察提供了肿瘤细胞中的第一个证据，表明TNF诱导的NF-κB活化具有抗凋亡功能，可能通过TNF和IFN-α之间的细胞因子串扰而被修饰为促凋亡功能。TNF/IFN-α和FasL可有效诱导肿瘤细胞凋亡，或联合上调FasL可能成为一种具有临床应用价值的肿瘤治疗新策略。

项目成果

Kimura M, Haisa M, Ueteuka H, Takaoka M, Ohkawa T, Kawashima R, Yamatsuji T, Gunduz M, Kaneda Y, Tanaka N, and Naomoto Y.: "TNF combined wilhIFN-α accelerates NF-κB-mediated apoplosis through enhancement of Fas expression in colon cancer cells"Cell Death

Kimura M、Haisa M、Ueteuka H、Takaoka M、Ohkawa T、Kawashima R、Yamatsuji T、Gunduz M、Kaneda Y、Tanaka N 和 Naomoto Y.：“TNF 与 IFN-α 结合可加速 NF-κB 介导的细胞凋亡通过增强结肠癌细胞中Fas的表达“细胞死亡”

Kimura M, Haisa M, et al.: "TNF combined with IFN-α accelerates NF-κB-mediated apoptosis through enhancement of Fas expression in colon cancer cells"Cell Death and Differentiation. 10. 718-738 (2003)

Kimura M、Haisa M 等人：“TNF 与 IFN-α 结合，通过增强结肠癌细胞中的 Fas 表达来加速 NF-κB 介导的细胞凋亡”，《细胞死亡与分化》(Cell Death and Differentiation)。