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

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

Submitted 29 August 2003 ; accepted in final form 24 October 2003

Peroxisome proliferator-activated receptor (PPAR) agonists, such as 15-deoxy-^12,14-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 NF-B 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 IB 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-1-stimulated 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.

peroxisome proliferator-activated receptor-; 15-deoxy-^12,14-prostaglandin J₂; inducible nitric oxide synthase; islet; inflammation

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