Evidence for Involvement of NF-kappaB in the Transcriptional Control of COX-2 Gene Expression by IL-1beta

Biochem Biophys Res Commun. 1997 Aug 8;237(1):28-32. doi: 10.1006/bbrc.1997.7064.

Abstract

The cyclooxygenase (COX) isoforms COX-1 and COX-2 convert arachidonic acid to prostaglandin (PG) precursors and are a limiting step in PG production. Interleukin-1beta (IL-1beta) treatment of type II A549 cells increases PGE2 synthesis via transcription- and translation-dependent induction of COX-2. IL-1beta produces a 10-fold induction of COX-2 mRNA and an 8-fold increase in COX-2 transcription that was temporally preceded by activation of the transcription factor nuclear factor-kappaB (NF-kappaB). The protein-tyrosine phosphatase inhibitor phenylarsine oxide (PAO) prevented both NF-kappaB activation and induction of COX-2 mRNA. We show that two putative NF-kappaB motifs, kappaBu (-447/-438) and kappaBd (-224/-214), from the COX-2 promoter bind p50/p65 NF-kappaB heterodimers in an IL-1beta-dependent manner and that the upstream element has the greater affinity. Finally, we demonstrate that the two NF-kappaB subunits, p50 and p65, synergistically activate a -917/+49 COX-2 promoter construct. We conclude that IL-1beta stimulates PG production via transcriptional activation of COX-2 and provide evidence that this may involve NF-kappaB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arsenicals / pharmacology
  • Base Sequence
  • Cell Nucleus / metabolism
  • Consensus Sequence
  • Cyclooxygenase 2
  • DNA Primers
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-1 / pharmacology*
  • Isoenzymes / biosynthesis*
  • Membrane Proteins
  • NF-kappa B / metabolism*
  • Oligodeoxyribonucleotides
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Protein Biosynthesis
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • RNA, Messenger / biosynthesis
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*
  • Tumor Cells, Cultured

Substances

  • Arsenicals
  • DNA Primers
  • Enzyme Inhibitors
  • Interleukin-1
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • RNA, Messenger
  • oxophenylarsine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein Tyrosine Phosphatases