PPAR is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic -cells

Weber, Sarah M., Anna L. Scarim, and John A. Corbett. PPAR is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic -cells. Am J Physiol Endocrinol Metab 286: E329–E336, 2004. First published November 4, 2003; 10.1152/ ajpendo.00392.2003.—Peroxisome proliferator-activated receptor (PPAR) agonists, such as 15-deoxy-prostaglandin J2 (PGJ2) and troglitazone, have been shown to elicit anti-inflammatory effects in pancreatic -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 NFB and MAPK as well as IFN-stimulated signal transducer and activator of transcription (STAT)1 activation in -cells. The purpose of this study was to determine if PPAR activation participates in the anti-inflammatory actions of PGJ2 in -cells. Pretreatment of RINm5F cells for 6 h with PGJ2 results in inhibition of IL-1-stimulated I B degradation and IFN-stimulated STAT1 phosphorylation. Overexpression of a dominant-negative (dn) PPAR mutant or treatment with the PPAR 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 PPAR response element reporter activity. Consistent with the inability to attenuate the inhibitory actions of PGJ2 on cytokine signaling, neither dnPPAR nor GW-9662 prevents the inhibitory actions of PGJ2 on IL-1stimulated iNOS gene expression or nitric oxide production by RINm5F cells. These findings support a PPAR -independent mechanism by which PPAR ligands impair cytokine signaling and iNOS expression by islets.