Selective inhibition of cyclooxygenase-2 expression by 15-deoxy-Delta(12,14)(12,14)-prostaglandin J(2) in activated human astrocytes, but not in human brain macrophages.
Overexpression of the inducible cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in activated brain macrophages (microglia) and astrocytes appears central to many neuroinflammatory conditions. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma. It has been proposed as an inhibitor of microglial activation, based on the study of iNOS down-regulation in rodent microglia. Because iNOS induction after cytokine activation remains controversial in human microglia, we examined the effect of 15d-PGJ(2) and other PPAR agonists on human microglia and astrocytes, using COX-2 induction as an index of activation. We found that PPAR alpha ligands (clofibrate and WY14643) enhanced IL-1 beta-induced COX-2 expression in human astrocytes and microglia, while inhibiting IL-1 beta plus IFN-gamma induction of iNOS in astrocytes. This is the first description of an inhibition of iNOS uncoupled from that of COX-2. 15d-PGJ(2) suppressed COX-2 induction in human astrocytes. It prevented NF-kappa B binding to the COX-2 promoter through a new pathway that is the repression of NF-kappa Bp50 induction by IL-1 beta. In contrast, 15d-PGJ(2) increased c-Jun and c-Fos DNA-binding activity in astrocytes, which may result in the activation of other inflammatory pathways. In human microglia, no effect of 15d-PGJ(2) on COX-2 and NF-kappa Bp65/p50 induction was observed. However, the entry of 15d-PGJ(2) occurred in microglia because STAT-1 and c-Jun expression was modulated. Our data suggest the existence of novel pathways mediated by 15d-PGJ(2) in human astrocytes. They also demonstrate that, unlike astrocytes and peripheral macrophages or rodent brain macrophages, human microglia are not subject to the anti-inflammatory effect of 15d-PGJ(2) in terms of COX-2 inhibition.
Janabi
Nazila
N
Laboratory of Molecular Medicine and Neuroscience, National Institutes of Health, Bethesda, MD 20892, USA. n.janabi@envt.fr
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D002994:Clofibrate; D015230:Prostaglandin D2