Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 286, Issue 3, Pages E329-E336Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00392.2003
Keywords
peroxisome proliferator-activated receptor-gamma; 15-deoxy-Delta(12,14)-prostaglandin J(2); inducible nitric oxide synthase; islet; inflammation
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Funding
- NIAID NIH HHS [AI-44458] Funding Source: Medline
- NIDDK NIH HHS [DK-52194] Funding Source: Medline
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Peroxisome proliferator-activated receptor (PPAR)gamma agonists, such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) and troglitazone. have been shown to elicit anti-inflammatory effects in pancreatic P-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 PGJ(2) in beta-cells. Pretreatment of RINm5F cells for 6 h with PGJ(2) results in inhibition of IL-1-stimulated IkappaB degradation and IFN-gamma-stimulated STATI phosphorylation. Overexpression of a dominant-negative (dn) PPARgamma mutant or treatment with the PPARgamma antagonist GW-9662 does not modulate the inhibitory actions of PGJ(2) on cytokine signaling in RINm5F cells. Although these agents fail to attenuate the inhibitory actions of PGJ(2) on cytokine signaling, they do inhibit PGJ(2)-stimulated PPARgamma response element reporter activity. Consistent with the inability to attenuate the inhibitory actions of PGJ(2) on cytokine signaling, neither dnPPARgamma nor GW-9662 prevents the inhibitory actions of PGJ(2) 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.
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