Cyclopentenone prostaglandins suppress activation of microglia: Down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta(12,14)-prostaglandin J(2)

Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of act ivated glia in neurodegeneration. Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions. We examin ed the influence of cyclopentenone prostaglandins and their precursors on a ctivated glia. As models of glial activation, production of inducible nitri c-oxide synthase (iNOS) was studied in lipopolysaccharide- stimulated rat m icroglia, a murine microglial cell line BV-2, and IL-1 beta-stimulated rat astrocytes. Cyclopentenone prostaglandins were potent inhibitors of iNOS in duction and were more effective than their precursors, prostaglandins E-2 a nd D-2, 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) was the most potent prostaglandin among those tested. In activated microglia, 15d-PGJ(2) suppressed iNOS promoter activity, iNOS mRNA, and protein levels. The acti on of 15d-PGJ(2) does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) because troglitazone, a specific ligand of PPAR gamma, was unable to inhibit iNOS induction, and n either troglitazone nor 15d-PGJ(2) could stimulate the activity of a PPAR-d ependent promoter in the absence of cotransfected PPAB gamma. 15d-PGJ(2) di d not block nuclear translocation or DNA-binding activity of the transcript ion factor NF kappa B, but it did inhibit the activity of an NP kappa B rep orter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ(2) may involve interference with NF kappa B transcriptiona l activity in the nucleus. Thus, our data suggest the existence of a novel pathway mediated by cyclopentenone prostaglandins, which may represent part of a feedback mechanism leading to the cessation of inflammatory glial res ponses in the brain.