Low-dose cytokine-induced neutral ceramidase secretion from INS-1 cells via exosomes and its anti-apoptotic effect
Low-dose cytokine-induced neutral ceramidase secretion from INS-1 cells via exosomes and its anti-apoptotic effect
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低剂量细胞因子诱导INS-1细胞通过外泌体分泌中性神经酰胺酶及其抗凋亡作用
DOI：
10.1111/febs.12826
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发表时间：
2014-06-01
期刊：
影响因子：
5.4
通讯作者：
He, Songqing
中科院分区：
文献类型：
--
作者：
Zhu, Qun;Kang, Jian;He, Songqing
据报道，炎症细胞因子对 1 型糖尿病中 β 细胞破坏的影响具有浓度依赖性。然而，其根本机制仍不清楚。在本研究中，我们发现高浓度的细胞因子促进大鼠β细胞系INS-1的细胞凋亡，而低浓度的细胞因子则没有作用。我们还发现，低浓度的细胞因子刺激INS-1细胞通过外泌体释放中性神经酰胺酶（NCDase），而高浓度的细胞因子则抑制NCDase的释放。此外，结果表明，从用低浓度细胞因子处理的INS-1细胞培养基中分离出的含有NCDase的外泌体抑制了高浓度细胞因子诱导的细胞凋亡。最后，结果还表明，外泌体中 NCDase 对细胞凋亡的保护作用是通过 1-磷酸鞘氨醇 (S1P) 的生成及其与 S1P 受体 2 的相互作用介导的。总之，这些发现揭示了一种新的 NCDase-S1P-磷酸盐-S1P 受体 2 依赖性机制，通过该机制，低水平的炎症细胞因子可以保护胰腺 β 细胞免受高水平炎症细胞因子诱导的细胞凋亡。
It has been reported that the effect of inflammatory cytokines on beta-cell destruction in type 1 diabetes is concentration-dependent. However, the underlying mechanisms remain unclear. In the present study, we found that a high concentration of cytokines promoted apoptosis in the rat beta-cell line INS-1, whereas a low concentration of cytokines had no effect. We also found that cytokines at a low concentration stimulated neutral ceramidase (NCDase) release via exosomes from INS-1 cells, whereas cytokines at a high concentration inhibited NCDase release. Furthermore, the results showed that the NCDase-containing exosomes isolated from the culture medium of INS-1 cells treated with cytokines at a low concentration inhibited apoptosis induced by a high concentration of cytokines. Finally, the results also showed that the protective action of NCDase in the exosomes on apoptosis was mediated by the generation of sphingosine 1-phosphate (S1P) and its interaction with S1P receptor 2. Taken together, these findings revealed a novel NCDase-S1P-phosphate-S1P receptor 2-dependent mechanism by which a low level of inflammatory cytokines protects pancreatic beta-cells from apoptosis induced by a high level of inflammatory cytokines.