Regulation of CCAAT/Enhancer-binding Protein Homologous Protein (CHOP) Expression by Interleukin-1 in Pancreatic Cells*

Apoptosis contributes to immune-mediated pancreatic cell destruction in type I diabetes. Exposure of cells to interleukin-1 (IL-1 ) causes endoplasmic reticulum stress and activates proapoptotic networks. Here, we show that nuclear factor B (NFB) and mitogen-activated protein kinase (MAPK) signaling pathways regulate the expression of CCAAT/enhancer-binding protein homologous protein (CHOP), which mediates endoplasmic reticulum stress-induced apoptosis. Both CHOP mRNA and protein increase in cells treated with IL-1 . In addition, prolonged exposure to high glucose further increases IL-1 -triggered CHOP expression. IL-1 also causes increased expression of C/EBPand a reduction of MafA, NFATc2, and Pdx-1 expression in cells. Inhibition of the NFB and MAPK signaling pathways differentially attenuates CHOP expression. Knocking down CHOP by RNA interference protects cells from IL-1 -induced apoptosis. These studies provide direct mechanistic links between cytokine-induced signaling pathways and CHOP-mediated apoptosis of cells.