Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
FEBS J. 2014 Jun;281(12):2861-70. doi: 10.1111/febs.12826. Epub 2014 May 15.
It has been reported that the effect of inflammatory cytokines on β-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 β-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 β-cells from apoptosis induced by a high level of inflammatory cytokines.
据报道，炎症细胞因子对 1 型糖尿病中β细胞破坏的影响呈浓度依赖性。然而，其潜在机制尚不清楚。在本研究中，我们发现高浓度细胞因子促进大鼠β细胞系 INS-1 的细胞凋亡，而低浓度细胞因子则没有作用。我们还发现，低浓度细胞因子通过 INS-1 细胞来源的外体刺激中性鞘氨醇酶（NCDase）释放，而高浓度细胞因子抑制 NCDase 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，外体中的 NCDase 在细胞凋亡中的保护作用是通过鞘氨醇 1-磷酸（S1P）的产生及其与 S1P 受体 2 的相互作用介导的。综上所述，这些发现揭示了一种新的 NCDase-S1P-磷酸-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防止高水平的炎症细胞因子诱导的胰腺β细胞凋亡。
