Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase

Nature. 2000 Jan 6;403(6765):103-8. doi: 10.1038/47520.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclopentanes
  • Enzyme Inhibitors
  • NF-kappa B
  • Prostaglandins A
  • Tumor Necrosis Factor-alpha
  • Arachidonic Acid
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Tetradecanoylphorbol Acetate
  • cyclopentenone
  • Prostaglandin D2
  • prostaglandin A1