TRAIL upregulates decoy receptor 1 and mediates resistance to apoptosis in insulin-secreting INS-1 cells

Abstract

TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating the homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. In particular, the potential role of TRAIL in type 1 diabetes (T1D) has been studied by several research groups. A previous study found that TRAIL did not have significant cytotoxic effects on the insulin-secreting pancreatic β cell line, INS-1. However, the mechanism was not clear. Here we demonstrate that INS-1 cells are resistant to TRAIL-induced apoptosis and show alteration in the expression of death and decoy receptors upon TRAIL treatment. To compare TRAIL-resistant INS-1 cells with TRAIL-sensitive cells, we utilized U87MG cells, which are known to be TRAIL-sensitive. TRAIL treatment showed NF-κB translocation to the nucleus in TRAIL-resistant INS-1 cells, and TRAIL-induced NF-κB activation was preceded by IκBα degradation. A pharmacological inhibitor of NF-κB, Bay 11-7082, blocked TRAIL-induced NF-κB translocation to the nucleus and IκBα degradation. Four related receptors bind TRAIL: two death receptors (DR4 and DR5) that promote apoptosis, and two decoy receptors (DcR1 and DcR2) that act as dominant-negative inhibitors of TRAIL-mediated apoptosis. In the present study, TRAIL treatment in INS-1 cells upregulated DcR1 and downregulated DR5 without altering the expression of DcR2 and DR4. The resistance to apoptosis in INS-1 cells might therefore, be a consequence of DcR1 upregulation and DR5 downregulation, and the transcription factor, NF-κB, could regulate the sensitivity of cells to TRAIL by controlling the ratio of decoy to death receptors. Thus, TRAIL may play an important role in the survival of pancreatic β cells by regulating receptor expression in an NF-κB-dependent manner.