Low-dose cytokine-induced neutral ceramidase secretion from INS-1 cells via exosomes and its anti-apoptotic effect

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.