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 beta 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-kappa B translocation to the nucleus in TRAIL-resistant INS-1 cells, and TRAIL-induced NF-kappa B activation was preceded by I kappa B alpha degradation. A pharmacological inhibitor of NF-kappa B, Bay 11-7082, blocked TRAIL-induced NF-kappa B translocation to the nucleus and I kappa B alpha 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-kappa B, 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 beta cells by regulating receptor expression in an NF-kappa B-dependent manner. (C) 2010 Elsevier Inc. All rights reserved.