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PPAR ligands induce ER stress in pancreatic -cells: ER stress activation results in attenuation of cytokine signaling

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

Submitted 26 July 2004 ; accepted in final form 16 August 2004

Peroxisome proliferator-activated receptor (PPAR) ligands are known to have anti-inflammatory properties that include the inhibition of cytokine signaling, transcription factor activation, and inflammatory gene expression. We have recently observed that increased expression of heat shock protein (HSP)70 correlates with, but is not required for, the anti-inflammatory actions of PPAR ligands on cytokine signaling. In this study, we provide evidence that the inhibitory actions of PPAR ligands on cytokine signaling are associated with endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation in pancreatic -cells. 15-Deoxy-^12,14-prostaglandin J₂, at concentrations that inhibit cytokine signaling, stimulates phosphorylation of eukaryotic initiation factor-2, and this event is followed by a rapid inhibition of protein translation. Under conditions of impaired translation, PPAR ligands stimulate the expression of a number of ER stress-responsive genes, such as GADD 153, BiP, and HSP70. Importantly, ER stress activation in response to PPAR ligands or known UPR activators results in the attenuation of IL-1 and IFN- signaling. These findings indicate that PPAR ligands induce ER stress, that ER stress activation is associated with an attenuation of cytokine signaling in -cells, and that the attenuation of responsiveness to extracellular stimuli appears to be a novel protective action of the UPR in cells undergoing ER stress.

unfolded protein response; interferon-; peroxisome proliferator-activated receptor-; endoplasmic reticulum

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