Faculty Collaboration Database

PPARgamma is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic beta-cells. Am J Physiol Endocrinol Metab 2004 Mar;286(3):E329-36

Date

11/06/2003

Pubmed ID

14600076

DOI

10.1152/ajpendo.00392.2003

Scopus ID

2-s2.0-1442349764 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Peroxisome proliferator-activated receptor (PPAR)gamma agonists, such as 15-deoxy-delta 12,14-prostaglandin J2 (PGJ2) and troglitazone, have been shown to elicit anti-inflammatory effects in pancreatic beta-cells that include inhibition of cytokine-stimulated inducible nitric oxide synthase (iNOS) gene expression and production of nitric oxide. In addition, these ligands impair IL-1-induced NF-kappaB and MAPK as well as IFN-gamma-stimulated signal transducer and activator of transcription (STAT)1 activation in beta-cells. The purpose of this study was to determine if PPARgamma activation participates in the anti-inflammatory actions of PGJ2 in beta-cells. Pretreatment of RINm5F cells for 6 h with PGJ2 results in inhibition of IL-1-stimulated IkappaB degradation and IFN-gamma-stimulated STAT1 phosphorylation. Overexpression of a dominant-negative (dn) PPARgamma mutant or treatment with the PPARgamma antagonist GW-9662 does not modulate the inhibitory actions of PGJ2 on cytokine signaling in RINm5F cells. Although these agents fail to attenuate the inhibitory actions of PGJ2 on cytokine signaling, they do inhibit PGJ2-stimulated PPARgamma response element reporter activity. Consistent with the inability to attenuate the inhibitory actions of PGJ2 on cytokine signaling, neither dnPPARgamma nor GW-9662 prevents the inhibitory actions of PGJ2 on IL-1-stimulated iNOS gene expression or nitric oxide production by RINm5F cells. These findings support a PPARgamma-independent mechanism by which PPARgamma ligands impair cytokine signaling and iNOS expression by islets.

Author List

Weber SM, 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
Dose-Response Relationship, Drug
Islets of Langerhans
Male
Mutagenesis, Site-Directed
Mutation
Prostaglandin D2
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear
Signal Transduction
Transcription Factors