IFN-gamma sensitizes MIN6N8 insulinoma cells to TNF-alpha-induced apoptosis by inhibiting NF-kappaB-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 beta-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-kappaB (NF-kappaB)-dependent pathway, and interferon (IFN)-gamma prevented such an induction in a manner independent of NF-kappaB, 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 beta-cell apoptosis and in the pathogenesis of type 1 diabetes.
Kim
Hun Sik
HS
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Kim
Sunshin
S
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D004357:Drug Synergism; D007340:Insulinoma; D007371:Interferon-gamma / Q000633:toxicity*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D007371:Interferon-gamma