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ligands induce ER stress in pancreatic 
-cells: ER stress activation results in the attenuation of cytokine signaling
1 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: corbettj{at}slu.edu.
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 antiinflammatory
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. PGJ2, at concentrations that inhibit cytokine signaling, stimulates phosphorylation of
eukaryotic initiation factor (eIF) 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 (CHOP), BiP, and hsp 70.
Importantly, ER stress activation in response to PPAR- ligands or known UPR activators results
in the attenuation of IL-1 and IFN-[[gammaa] 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.
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