Enhancement of tumoricidal activity of microglial cell via CD40-CD40 ligand interaction

通过 CD40-CD40 配体相互作用增强小胶质细胞的杀肿瘤活性

• 批准号: 13470288
• 负责人: MORI Hiroshi
• 金额: $ 1.15万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470288/
• 关键词: microglia; glioma; CD40; IL-12; TNF-α; NO; γ-INF; IL-2; cell therapy

Purpuse) It has been reported that CD40-CD40 ligand (CD40L) interaction plays key role for cell mediated immunity on microglial cell as macropharge and dendritic cell. So we examined whether antitumor activity of microglial cell could be enhanced via CD40 induced microglial cell cocultured with CD40L transfected 203 glioma cell lines.Result) Microglial clone derived form neoborn mouse induced CD40 by combined stimulation of LPS and Interferon (IFN)-g. The following stimulation of soluble CD 40 ligand enhanced TNF-a and NO production of microglia. The supernatants from stimulated microglia via CD 40 ligation mediated killing effect against CD40 transfected 203 glioma cell line as compared to that of the stimulation by LPS, IFN-g, or LPS and IFN-g. Individually applied during CD40 ligation, anti CD40 ligand, antagonists TNF-a, or L-MNNA, or as pairs (anti TNF-a and L-MNNA) inhibited killing activity of the supernatants from stimulated microglia. This indicate that a mixture of the TNF-a and NO, or TNF-a, NO, and other factor(s) mediated significant apoptosis in tumor cell. These findings demonstrate that microglial cells induce apoptosis in tumor cells by at least two of these cytotoxic factors via CD40 engagement.

CD40-CD40配体(CD40L)相互作用在巨噬细胞和树突状细胞等小胶质细胞的细胞免疫中起关键作用。因此，我们检测了CD40诱导的小胶质细胞与转导CD40L的203个胶质瘤细胞株共培养能否增强小胶质细胞的抗肿瘤活性。结果)新生鼠来源的小胶质细胞克隆在脂多糖和干扰素-g联合刺激下诱导CD40。随后刺激可溶性CD40配体可增加小胶质细胞产生肿瘤坏死因子-α和一氧化氮。CD40刺激的小胶质细胞培养上清液对转CD40的203胶质瘤细胞的杀伤作用与脂多糖、干扰素-g或脂多糖和干扰素-g的刺激作用相比较。CD_(40)结扎过程中单独应用抗CD_(40)配体、拮抗剂肿瘤坏死因子-α或L-MNNA，或成对应用(抗肿瘤坏死因子-α和L-MNNA)可抑制刺激的小胶质细胞培养上清液的杀伤活性。这表明，肿瘤坏死因子-α与一氧化氮或肿瘤坏死因子-α、一氧化氮等因子(S)共同介导了肿瘤细胞的显著凋亡。这些发现表明，小胶质细胞通过CD40参与至少两种细胞毒因子诱导肿瘤细胞的凋亡。