Peroxisome Proliferator-Activated Receptor (PPAR)- ligands have been shown to possess anti-inflammatory properties that include the inhibition of transcription factor activation and the expression of inflammatory genes. Using pancreatic -cells, we have shown that PPAR- ligands such as PGJ₂ attenuate IFN--induced STAT1 activation and IL-1-induced nuclear factor (NF)-B activation by a pathway that correlates with endoplasmic reticulum (ER) stress and the induction of the Unfolded Protein Response (UPR). The UPR is a conserved cellular stress response activated by a number of cell stressors and is believed to alleviate the stress and promote cell survival. However, prolonged activation of the UPR results in cellular death by apoptosis. In this report we have examined the effects of PGJ₂ on UPR activation and the consequences of this activation on cell survival. Consistent with induction of a cell death pathway, treatment of rat islets and RINm5F cells for 24 h with PGJ₂ results in caspase-3 activation and caspase-dependent -cell death. The actions of these ligands do not appear to be selective for -cells, as PGJ₂ stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eIF2, and in cells expressing a mutant of eIF2 that cannot be phosphorylated, the stimulatory actions of PGJ₂ on caspase-3 activation are augmented. These findings suggest that while PGJ₂-induced UPR activation is associated with an inhibition of cytokine signaling, prolonged UPR activation results in cell death, and that eIF2 phosphorylation may function in a protective manner to attenuate cell death.