Positive and negative regulation of NF-kappaB by COX-2: roles of different prostaglandins

J Biol Chem. 2001 Oct 19;276(42):38658-64. doi: 10.1074/jbc.M106599200. Epub 2001 Aug 16.

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.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Binding Sites
  • Blotting, Northern
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclooxygenase 2
  • Cytoplasm / metabolism
  • Dinoprostone / physiology
  • Down-Regulation
  • Enzyme Activation
  • Gene Expression Regulation*
  • Genetic Vectors
  • Humans
  • I-kappa B Kinase
  • Inflammation
  • Interleukin-8 / metabolism
  • Isoenzymes / metabolism*
  • Luciferases / metabolism
  • Membrane Proteins
  • Models, Biological
  • NF-kappa B / metabolism*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Prostaglandins / physiology*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Interleukin-8
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Prostaglandins
  • Luciferases
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Dinoprostone