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      Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.

      Nature

      pharmacology, Amino Acid Sequence, antagonists & inhibitors, Tumor Necrosis Factor-alpha, Tetradecanoylphorbol Acetate, Protein-Serine-Threonine Kinases, Prostaglandins A, analogs & derivatives, Prostaglandin D2, metabolism, NF-kappa B, Molecular Sequence Data, Jurkat Cells, I-kappa B Kinase, Humans, HeLa Cells, Enzyme Inhibitors, Enzyme Activation, Cyclopentanes, COS Cells, Arachidonic Acid, Anti-Inflammatory Agents, Non-Steroidal, Animals

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          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.

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          Journal
          10.1038/47520
          10638762

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