15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway

Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4844-9. doi: 10.1073/pnas.97.9.4844.

Abstract

Prostaglandin J(2) (PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of prostaglandin D(2) that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor alpha, in a PPARgamma-dependent manner. We report here that 15d-PGJ(2) potently inhibits NF-kappaB-dependent transcription by two additional PPARgamma-independent mechanisms. Several lines of evidence suggest that 15d-PGJ(2) directly inhibits NF-kappaB-dependent gene expression through covalent modifications of critical cysteine residues in IkappaB kinase and the DNA-binding domains of NF-kappaB subunits. These mechanisms act in combination to inhibit transactivation of the NF-kappaB target gene cyclooxygenase 2. Direct inhibition of NF-kappaB signaling by 15d-PGJ(2) may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cyclooxygenase 2
  • Cyclopentanes / pharmacology
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Humans
  • Isoenzymes / genetics*
  • Membrane Proteins
  • NF-kappa B / metabolism*
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandins A / pharmacology
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transfection

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Cyclopentanes
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Prostaglandins A
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Transcription Factors
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Glutathione Transferase
  • prostaglandin A2
  • Tetradecanoylphorbol Acetate
  • cyclopentenone
  • Prostaglandin D2