title: Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.
abstract: NF-kappaB is a critical activator of genes involved in inflammation and immunity. Pro-inflammatory cytokines activate the IkappaB kinase (IKK) complex that phosphorylates the NF-kappaB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation. Freed NF-kappaB dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation. Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma. Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKKbeta subunit of IKK. As IKKbeta is responsible for the activation of NF-kappaB by pro-inflammatory stimuli, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.
authors.affiliation: Institute of Experimental Medicine, Italian National Council of Research, University of Rome Tor Vergata, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: P
authors.initials: P
authors.lastname: Kapahi
authors.forename: G
authors.initials: G
authors.lastname: Natoli
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Karin
authors.forename: M G
authors.initials: MG
authors.lastname: Santoro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D019556:COS Cells; D003517:Cyclopentanes / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011454:Prostaglandins A; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D013755:Tetradecanoylphorbol Acetate; C013905:cyclopentenone; D015230:Prostaglandin D2; C100573:prostaglandin A1