title: Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2.
abstract: Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of activated glia in neurodegeneration. Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions. We examined the influence of cyclopentenone prostaglandins and their precursors on activated glia. As models of glial activation, production of inducible nitric-oxide synthase (iNOS) was studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell line BV-2, and IL-1beta-stimulated rat astrocytes. Cyclopentenone prostaglandins were potent inhibitors of iNOS induction and were more effective than their precursors, prostaglandins E2 and D2. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) was the most potent prostaglandin among those tested. In activated microglia, 15d-PGJ2 suppressed iNOS promoter activity, iNOS mRNA, and protein levels. The action of 15d-PGJ2 does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) because troglitazone, a specific ligand of PPARgamma, was unable to inhibit iNOS induction, and neither troglitazone nor 15d-PGJ2 could stimulate the activity of a PPAR-dependent promoter in the absence of cotransfected PPARgamma. 15d-PGJ2 did not block nuclear translocation or DNA-binding activity of the transcription factor NFkappaB, but it did inhibit the activity of an NFkappaB reporter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ2 may involve interference with NFkappaB transcriptional 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 responses in the brain.
authors: Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors: T V
authors: TV
authors: Petrova
authors: K T
authors: KT
authors: Akama
authors: L J
authors: LJ
authors: Van Eldik
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D003001:Cloning, Molecular; D011464:Epoprostenol / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012486:Salmonella typhimurium; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015230:Prostaglandin D2