Investigation of the apoptotic effect of TRAIL on insulinoma derived mouse beta cell lines

Destruction of pancreatic beta cells during the course of progressive insulitis by the effects of proinflammatory cytokines is well acknowledged in Type 1 Diabetes (T1D). Besides TNF and FasL, IFN-gamma and IL-1beta have also been correlated with beta cell deaths in T1D development. It was shown, on the other hand, that another TNF family member, TNF-Related Apoptosis Inducing Ligand (TRAIL), which was discovered in 1995, could suppress autoimmune responses. However, there are also indications on TRAIL's possible destructive role on beta cells as well. Thus, the precise effect of TRAIL on beta cells, and its general role in T1D is not yet fully revealed. Our results showed that among the TRAIL transmembrane receptors, DR5 is expessed at the highest level on the NIT-1 mouse beta cell lines, while the substantial expression of DcR1 and DcR2 decoy receptors is also evident. We detected that the soluble form of TRAIL (sTRAIL) displayed an intermediate level of cytotoxicity in NIT-1 cells. When applied together with the proinflammatory cytokines TNF, IFN-gamma, and IL-1beta, TRAIL increased cell death in short term (24 hours), while no additional cytotoxic effect to that of the proinflammatory cytokines was observed in longer term (48 hours), along with some protective effect as well. In accordance with these findings, DR5 death receptor expression was suppressed at 48 hours with the effect of the inflammatory cytokines. We also observed suppressed TRAIL ligand expression on NIT-1 cells at 24 and 48 hours by application of proinflammatory cytokines. Our results indicate that cytotoxicity caused by the proinflammatory cytokines was increased in NIT-1 pancreatic beta cell lines after simultaneous exposure to TRAIL ligand in short term. Later on in longer term, TRAIL displayed no additional cytotoxic effect, and also acted in a protective manner at some extent. We believe that our results will contribute to the better understanding of TRAIL's role in T1D.