PPARgamma is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic beta-cells.
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.
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
Sarah M
SM
Weber
Anna L
AL
Scarim
John A
JA
Corbett
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007515:Islets of Langerhans; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000145:classification / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D014157:Transcription Factors / Q000145:classification / Q000378:metabolism*
D016207:Cytokines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2