Faculty Collaboration Database

PPARgamma ligands induce ER stress in pancreatic beta-cells: ER stress activation results in attenuation of cytokine signaling. Am J Physiol Endocrinol Metab 2004 Dec;287(6):E1171-7

Date

08/19/2004

Pubmed ID

15315910

DOI

10.1152/ajpendo.00331.2004

Scopus ID

2-s2.0-8544267219 (requires institutional sign-in at Scopus site)   64 Citations

Abstract

Peroxisome proliferator-activated receptor (PPAR)gamma 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 PPARgamma ligands on cytokine signaling. In this study, we provide evidence that the inhibitory actions of PPARgamma ligands on cytokine signaling are associated with endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation in pancreatic beta-cells. 15-Deoxy-Delta(12,14)-prostaglandin J(2), at concentrations that inhibit cytokine signaling, stimulates phosphorylation of eukaryotic initiation factor-2alpha, and this event is followed by a rapid inhibition of protein translation. Under conditions of impaired translation, PPARgamma 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 PPARgamma ligands or known UPR activators results in the attenuation of IL-1 and IFN-gamma signaling. These findings indicate that PPARgamma ligands induce ER stress, that ER stress activation is associated with an attenuation of cytokine signaling in beta-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.

Author List

Weber SM, Chambers KT, Bensch KG, Scarim AL, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cytokines
Endoplasmic Reticulum
Eukaryotic Initiation Factor-2
Gene Expression
Islets of Langerhans
Ligands
PPAR gamma
Phosphorylation
Prostaglandin D2
Protein Folding
Proteins
Rats
Rats, Sprague-Dawley
Signal Transduction
Stress, Physiological