IFN-γ sensitizes MIN6N8 insulinoma cells to TNF-α-induced apoptosis by inhibiting NF-κB-mediated XIAP upregulation

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 β-cell apoptosis remains unclear. Here, we found that: (i) XIAP level was inversely correlated with tumor necrosis factor (TNF)-α-induced apoptosis in MIN6N8 insulinoma cells; (ii) adenoviral XIAP overexpression abrogated the TNF-α-induced apoptosis through inhibition of caspase activity; (iii) downregulation of XIAP by antisense oligonucleotide or Smac peptide sensitized MIN6N8 cells to TNF-α-induced apoptosis; (iv) XIAP expression was induced by TNF-α through a nuclear factor-κB (NF-κB)-dependent pathway, and interferon (IFN)-γ prevented such an induction in a manner independent of NF-κB, which presents a potential mechanism underlying cytotoxic IFN-γ/TNF-α synergism. Taken together, our results suggest that XIAP is an important modulator of TNF-α-induced apoptosis of MIN6N8 cells, and XIAP regulation in pancreatic β-cells might play an important role in pancreatic β-cell apoptosis and in the pathogenesis of type 1 diabetes.