title: Positive and negative regulation of NF-kappaB by COX-2: roles of different prostaglandins.
abstract: The prostaglandin H synthases (PGHS) catalyze the conversion of arachidonic acid to prostaglandin H(2), the committed step in prostanoid synthesis. Two forms of PGHS exist, PGHS-1 (COX-1) and PGHS-2 (COX-2). The gene encoding the latter form is known to be inducible by a number of stimuli including several inflammatory mediators. Recent evidence indicates that the inducible cyclooxygenase may have both pro- and anti-inflammatory properties through the generation of different prostaglandins. Previous reports indicate that the transcription factor NF-kappaB can function upstream of COX-2 to control transcription of this gene and that the cyclopentenone prostaglandins can inhibit NF-kappaB activation via the inhibition of the IkappaB kinase. Thus, it is suggested that cyclopentenones feed back to inhibit continued nuclear accumulation of NF-kappaB. In this report we demonstrate COX-2 expression inhibits nuclear translocation of NF-kappaB, and we confirm that the cyclopentenone prostaglandins inhibit NF-kappaB. In addition, we show that prostaglandin E(2) and its analogs promote the inherent transcriptional activity of the p65/RelA subunit of NF-kappaB in a manner independent of induced nuclear accumulation. Consistent with this evidence, prostaglandin E(2) strongly synergizes with the inflammatory cytokine tumor necrosis factor-alpha to promote NF-kappaB-dependent transcription and gene expression. The data provide a molecular rationale to explain both the pro- and anti-inflammatory nature of COX-2.
authors.affiliation: Curriculum in Molecular Biology and Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: B
authors.initials: B
authors.lastname: Poligone
authors.forename: A S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D021581:Active Transport, Cell Nucleus; D001665:Binding Sites; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000378:metabolism; D015232:Dinoprostone / Q000502:physiology; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011453:Prostaglandins; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D015232:Dinoprostone