HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/E1052    most recent 00274.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chambers, K. T. Articles by Corbett, J. A. Search for Related Content PubMed PubMed Citation Articles by Chambers, K. T. Articles by Corbett, J. A.

PGJ₂-stimulated -cell apoptosis is associated with prolonged UPR activation

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

Submitted 7 June 2006 ; accepted in final form 16 November 2006

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 15-deoxy-^12,14-prostaglandin J₂ (PGJ₂) attenuate interferon--induced signal transducer and activator of transcription 1 activation and interleukin (IL)-1-induced nuclear factor-B activation by a pathway that correlates with endoplasmic reticulum stress and the induction of the unfolded protein response (UPR). The UPR is a conserved cellular 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, because PGJ₂ stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eukaryotic initiation factor 2 (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, whereas 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.

15-deoxy-^12,14-prostaglandin J₂; unfolded protein response; signaling