Although X-linked inhibitor of apoptosis protein (XIAP) is an important intracellular suppressor of apoptosis in a variety of cell types, its role in cytokine-induced pancreatic P-cell apoptosis remains unclear. Here, we found that: (i) XIAP level was inversely correlated with tumor necrosis factor (TNF)-alpha-induced apoptosis in MIN6N8 insulinoma cells; (ii) adenoviral XIAP overexpression abrogated the TNF-alpha-induced apoptosis through inhibition of caspase activity; (iii) downregulation of XIAP by antisense oligonucleotide or Smac peptide sensitized MIN6N8 cells to TNF-alpha-induced apoptosis; (iv) XIAP expression was induced by TNF-alpha, through a nuclear factor-kappa B (NF-kappa B)-dependent pathway, and interferon (IFN)-gamma prevented such an induction in a manner independent of NF-kappa B, which presents a potential mechanism underlying cytotoxic IFN-gamma/TNF-alpha synergism. Taken together, our results suggest that XIAP is an important modulator of TNF-alpha-induced apoptosis of MIN6N8 cells, and XIAP regulation in pancreatic beta-cells might play an important role in pancreatic P-cell apoptosis and in the pathogenesis of type 1 diabetes. (c) 2005 Elsevier Inc. All rights reserved.